I just did this drive over Memorial Day, and in fact it prompted the creation of this blog.
Driving from the Bay Area to South Lake Tahoe, there are two (well, let's make it three) major options. The most popular route is to get to Sacramento, then go east on Route 50. Or you can get to Stockton and go east on Route 88. The third option is to take I-80 northeast, which gets you to north Lake Tahoe, then drive around the lake to get to South Lake Tahoe.
The Long Way Around: I-80
I cannot vouch entirely for the third option. I've taken the I-80 route a few times, and it has its moments of heights, but at least it's an interstate. Once you get to Truckee, you have a choice: take 267 to 28 to 50 (east around the lake) or take 89 (west around the lake). The former option is definitely flatter, but longer. The latter option has one major scary section: Emerald Bay. It's beautiful, but precipitous, and a 2-lane road. There's one section where the road is atop a ridge separating Emerald Bay from Cascade Lake, about a 600-foot drop on both sides, and no guard rails. Luckily, the section is only a quarter-mile long, but yikes! I wouldn't want to try this in icy conditions.
The Fastest Way: Route 50
Most of this drive is quite easy. There's a bit of mild heights between Camino and Pollock Pines, but this acrophobe (at least) found it quite acceptable, and it's a stretch of only about two miles. After Pollock Pines, you drive along a valley for miles and miles. Even after climbing out of the valley, it's easy flat road.
Then you hit the Nebelhorn. This is the bit to fear: it's a stretch of about a mile with a 1000-foot cliff to the east. Some mitigating factors: the guardrails are excellent, and drivers don't rush: I took it at 30 mph and everyone around me seemed fine with that speed. At that speed you're past the worst of it in two minutes, and from there it's five minutes of (much less scary) heights until you're in the flat Tahoe Valley.
The Alternate Route: Route 88
Driving back from South Lake Tahoe to the Bay Area, we looked at the traffic on Route 50 (bear in mind this was Memorial Day and thus a day of heavy traffic) and looked for alternatives. The obvious one is Route 88. Not having scouting it ahead of time, Mrs. Acrophobe looked it up and read a review calling it a "lovely, well-maintained road that is curvy but not scary."
Well. I cannot argue with "well-maintained", and "curvy" is accurate. But "not scary"? Not quite. There are a number of passes and cliffside roads, and other drivers seem to feel comfortable taking them at 50 mph. Once coming over the passes, it's a long curvy drive along a ridge. It turns out this part isn't too bad: most of it is well away from the dropoffs, but not knowing the road, I was constantly worried that the next turn would lead over a cliff, so I kept my speed down, which pissed off the other drivers to no end.
The Verdict
At my level of acrophobia, Route 50 is the way to go. There's just the one bad stretch, and it's short and contained. You get it all over at once and can take it slow. Route 88 is out: too many passes, much too high. (Note that taking I-88 east of Stockton to about Jackson is beautiful and enjoyable, and not the sort of country you'll see much of in California, especially from the interstate. It's only scary once climbing into the mountains.) The third option, I-80, is in my opinion not worth the extra distance.
I hope this has been helpful. I'll be back soon with more driving tips!
