Parts of the Lakes Region  can be visited on a day trip from San Cristóbal , and that is still the most common option. Tour agencies offer all-day outings that include stops in Lagunas de Montebello  and El Chiflón  waterfall (and sometimes the pottery village of Amatenango del Valle  on the way back). Although it makes for a long day, it’s a logical option if your time is short.
You’ll enjoy the area much more, however, by basing yourself in Comitán , two hours east of San Cristóbal. A friendly and oft-overlooked city, Comitán  has excellent museums, plazas, and architecture, and great value in lodging and restaurants. In fact, plan on arriving early so you’ll have a full day to enjoy this “mini San Cristóbal” (just don’t call it that to locals!).
From there, you can still visit Lagunas de Montebello and El Chiflón as a day trip, or two days if you include the Maya ruins of Tenam Puente  and Chinkultik , with far less driving time than from San Cristóbal.
Staying in Comitán also gives you a jump on getting to more remote attractions east of Lagunas de Montebello, namely Las Guacamayas  and Las Nubes  eco-centers, and the isolated and gorgeous Laguna Miramar . The first and last are especially lovely, and worth budgeting at least two nights apiece. All can be reached fairly easily by public transportation, though having a car certainly makes getting around quicker and more efficient.
Beyond Las Guacamayas, you can continue from the Lakes Region up and around to the Río Usumacinta Valley  (including Yaxchilán  and Bonampak  archaeological sites) and eventually to Palenque . The roads are quite good, but combi service can be a bit spotty—you may have to leap-frog a bit leaving Las Guacamayas. Still, it’s a great way to reach Palenque without backtracking.