Cancer is essentially caused by alterations in normal cellular genes. Multiple gene changes involving at least two types of cancer genes, protooncogenes and tumor suppressor genes, are required for the clonal expansion of a malignant cell. This discussion focuses on the recently recognized role of a small but expanding family of PR-domain genes in tumorigenesis. The protein products of these genes are involved in human cancers in an unusual yin-yang fashion. Two products are normally produced from a PR-domain family member which differ by the presence or absence of the PR domain; the PR-plus product is disrupted or underexpressed whereas the PR-minus product is present or overexpressed in cancer cells. This imbalance in the amount of the two products, a result of either genetic or epigenetic events, appears to be an important cause of malignancy.