One of the most important physicochemical properties of small molecules and macromolecules are the dissociation constants for any weakly acidic or basic groups, generally expressed as the pKa of each group. This is a major factor in the pharmacokinetics of drugs and in the interactions of proteins with other molecules. For both the protein and small molecule cases, we survey the sources of experimental pKa values and then focus on current methods for predicting them. Of particular concern is an analysis of the scope, statistical validity, and predictive power of methods as well as their accuracy.