The SV40 early region protein, SV40 small t antigen, promotes cell transformation through negative regulation of the protein phosphatase 2A (PP2A) family of serine–threonine phosphatases. More recently, reduced levels of PP2A activity have been found in different types of human cancer. This occurs either through inactivating mutations of PP2A structural subunits, or by upregulation of the cellular PP2A inhibitors, CIP2A and SET. Several distinct PP2A complexes have been identified that contribute directly to tumor suppression by regulating specific phosphorylation events. These studies provide us with new insights into the role of protein phosphatases in cancer initiation and maintenance.