My brother and I drove a Toyota 4Runner from San Francisco, California to Tierra del Fuego and back, between March 9 and July 15, 1996. Below are some general observations you may find useful if you're planning a similar trip.
For a long drive, consider a diesel-powered vehicle. Local mechanics are familiar with diesel, the fuel is available everywhere, is generally quite a bit cheaper, and fuel consumption is much less compared with gasoline. I figure our 31,000 mile drive would have been about US$2000 cheaper in a diesel car.
In the Peruvian and Bolivian Andes one may only find 84 octane gas, but since air at 10,000 feet and above has less oxygen there is none of the pinging and knocking you expect at lower altitudes using low octane fuel.
Some roads are very rough (huge pot-holes, miles of washboard, etc.), so the car gets a real shaking. Fragile accessories like electric windows and CD players don't take the dust and shaking very well. Make it a habit to check around under the hood and beneath the car once a day just to make sure nothing is coming loose.
Automobile models are different enough in SA that you may not find the correct parts for your vehicle. Bring your own spare fuel, oil and air filters, spark plugs, distributor cap, fan belts, etc. Most basic Japanese and American car makes are seen throughout Latin America. We were surprised to find that Toyota does no business in Mexico (Nissan has it all!), so try not to break down in a Toyota in Mexico. On the other hand, Latin American mechanics can be very ingenious, devising home-made solutions to at least get you on your way.
Fuel in SA is often dirty; try to find new-looking gas (petrol) stations, as the storage tanks are less likely to have a layer of rusty water in the bottom. Bring some bottles of various fuel additives to remove water, clean fuel system, boost octane.
Four-wheel drive is not really necessary in SA, though it will allow you to be more adventuresome off the main highways. We drove 31,000 miles in SA on ordinary highway tires (ie: not off-road tires), and had only three punctures. Bring a couple of inner tubes; some holes may not be fixable by the locals even if the tire is basically ok. Also, if you bend a wheel rim on a bad pot-hole, a tubeless tire won't hold air. We even brought a spare wheel, though we didn't use it.
Vehicle security: Try to find secure parking each night. Most every town in SA has at least one attended parking lot, to which you will be referred by your hotel. Bolt a sturdy, padlocked metal box inside your car to protect stuff you really don't want to lose. Locking wheel lug nuts (don't lose the key!), a chain around any exterior spare wheels, and a hidden switch that deactivates your ignition, are all cheap devices to help you sleep better. And perhaps a car alarm, and locking gas cap.
Much of SA is a land of streets with no names, or at least no labels. Since populations are generally not as mobile as in Europe or the USA, and because car ownership is the exception, governments at all levels don't expend much energy on "signals, letreiros y placas." Those who drive professionally (bus, taxi and truck drivers) learn their way via apprenticeship, and those few people with private cars know their own neighborhoods. Maps may not be understood by professional drivers, much less the average citizen. All this makes life difficult for foreign drivers.
Continually ask when in doubt, and be selective of who you ask. Taxi, bus and truck drivers, and men wearing ties or carrying papers (ie: educated) are good bets. In general, do not ask indigenous peoples, women, or other obvious non-drivers; they just don't understand what a driver needs for directions, and are likely to lead you astray, with the best of intentions. Remember that "derecho" means straight ahead and "derecha" means to the right, even if they sound the same in rapid-fire spanish. Learn to disengage verbal instructions from the apparently contradictory hand signals that accompany them.
Countries with high crime rates include Guatamala, El Salvador, Nicaragua and Colombia, so caution is required. This means don't drive at night, stay at a hotel (no camping!), be aware of where you are and where the bad areas are, and have your car in protected parking lots at night.
Even though a car with foreign plates makes you more obvious, I believe you are not as subject to petty street crime as someone on foot. Most thieves, robbers, crooked taxi drivers, etc. hang out at train and bus stations, waiting for back-packers and other tourists. In a car you just aren't exposed to the majority of these hazards. You are also able to look more like a "normal citizen", at least from a distance; you don't have to carry all your stuff on your back; you are less encumbered when walking, thus less vulnerable a target. The downside is the responsibility of having the car, keeping it running, getting it across the Darien Gap, etc. But then, in a car you can go places that trains and buses would never take you. So it's a balance...
Border crossings in South America are generally pretty straight forward, especially if you have a libreta.
However, Central American border crossings can be very trying, with much confusion, delay, and extortion. Touts swarm you as you approach the border, offering (demanding!) to be your guide through the bureaucracy. Often the touts are in league with border officials, to ensure that maximum bribes are paid. Patience, firmness and negotiating skills are required. You generally deal with different officials for Immigration, Customs, Police, and sometimes Agriculture (fumigation, quarantine).
One of the most useful documents we possessed was an extensive typewritten list of every item in our car, including every spare part, roll of film, item of clothing, etc. The list was so overwhelmingly extensive that most Customs officials didn't bother to search the car, and just waved us onward. DO NOT itemize your finances on the list, though, as that would be just too tempting for any border official.
Money changers are found at every border. Talk to more than one to get a better rate. Although most changers are reasonably honest, use your own calculator to check the arithmetic. At the Ecuador-Peru border I fell for the old trick in which the buttons on the money changer's calculator were switched, giving a false calculation in favor of the changer.
Mosquitos, sandflies: Malaria and dengue fevers are real concerns in some areas, and the first line of defence is prevention of insect bites. Mosquito nets are effective, but are often a nuisance to set up, as you need anchor points to hang the net from; the fan over your bed can't be used if it's the anchor for your net; etc...
Poor Man's Insect Armor: Get a "sleeping sheet" a sleeping-bag-shaped sack made from bed sheeting, available from youth hostel supply or camping shops. From the same camping shop, buy an aerosol can of permethrin, (a synthetic pyrethrin, the active ingredient in mosquito coils), a repellant normally used to treat clothing. Spray the sheet with permethrin, rendering it unpalateable to 'skeeters and other biting insects. The treatment is good for three washings or so before respraying. Sleep in relatively cool comfort, with just your nose protruding for air, almost anywhere: in a bed, a hammock, on a train bench, boat deck, etc.