By Bus -- There are no express or luxury buses to Santiago de Atitlán. If you're coming by bus, your best bet is to head to Panajachel first, and then catch a boat taxi to Santiago de Atitlán (below). Santiago does have regular "chicken bus" service to and from Guatemala City. From Santiago, they leave from in front of the main plaza, roughly every hour between 4am and 3pm. Ask your hotel, or contact Asistur (tel. 1500) for current schedules.
By Boat -- From Panajachel, the docks for boats to Santiago de Atitlán are found at the public docks and beach area below the end of Calle Santander. The boats operate roughly every hour from around 6am until 5pm; however, if you're coming back to Panajachel, try to grab a boat by 4pm, as service after that becomes less frequent and less reliable. Schedules change according to demand, but you should never have to wait more than an hour to find a boat heading in your direction. Alternatively, you can hire an entire boat (which holds 10-12 people) to make the trip for around Q300 ($40/£20).
Boat taxis, their captains, and street touts almost always try to gouge tourists. There is a price difference between what locals pay and what tourists pay, and it's often hard to get a firm sense of what the official rates are or should be. Always ask your hotel or the INGUAT office about current fares before heading to the docks, and then try to be polite but firm in sticking to those guidelines.
A boat taxi between Panajachel and Santiago de Atitlán should cost around Q25 ($3.35/£1.65) each way. Between Santiago and San Pedro the ride should run Q15 ($2/£1). Note: Only pay for the leg of the ride you are actually taking. There is absolutely no reason to reserve a return trip in advance, and you run the risk of not meeting up with that specific boat or captain at the appointed time and losing your fare.
By Car -- The best route to drive here from Guatemala City is via the Pacific Highway (CA-2). From the Coastal Highway, turn right at Cocales, through the towns of Patutlul and San Lucas Tolimán.
Driving from Antigua, the best route is via the Pan-American Highway (CA-1). Take this road to Las Trampas, where you'll turn left toward Godinez. Drive through Aguas Escondidas and on to San Lucas Tolimán.
Santiago is quite compact, and aside from the challenge presented by its steep hill, you should be able to walk anywhere in town. Still, you can always find a taxi or tuk tuk near the dock to take you to the center of town for around Q5 (65¢/35p). A taxi to Posada Santiago or El Bambu should run you Q15 ($2/£1).
The boat taxis all land at a busy dock area at the foot of town. Just off the dock area and all along the steep cobblestone road leading up to the center of town, you'll find scores of makeshift stands and stores selling local arts and crafts. The main church and central plaza are at the top of this steep road. There are Banrural and Banco G&T Continental branches near the main plaza in Santiago; both have ATMs.