Many proteins involved in signal transduction and vesicle trafficking contain C2 domains whose membrane association is often regulated by calcium. Here, finite-difference Poisson-Boltzmann calculations are used to describe the electrostatic interactions between C2 domains of known structure and phospholipid membranes. The results explain how calcium binding can drive the association of some C2 domains to negatively charged membranes and others to neutral, zwitterionic membranes. Nonspecific electrostatic interactions are shown to be a general feature of many C2 domains of known structure, including the calcium-independent C2 domain of the PTEN tumor suppressor.