Adding to the difficulty of interpreting the human genome sequence and annotating protein sequence databases is the observation that a single protein can 'moonlight' or perform multiple, apparently unrelated, functions. This review summarizes examples of moonlighting proteins in cellular activities and biochemical pathways important in cancer and other diseases. The proteins include a variety of combinations of functions and mechanisms to switch between functions. Moonlighting proteins can be beneficial to the organism, such as by coordinating cellular activities. However, moonlighting proteins can potentially make more difficult the determination of the molecular mechanisms of disease and the process of rational drug design.