Familial cancer syndromes reflect an inherited predisposition to develop benign and malignant tumors. Clinically, the cancers occur at an earlier age and involve multiple foci of tumor formation at multiple sites. In the past 10 years, the molecular basis of many of these cancer syndromes have been unraveled with the advent of powerful genetic technologies. Entities which were hypothesized to be related on the basis of clinical features have now been shown to be linked or disparate through genetic analysis. This article reviews some of the recent advances in the clinical and molecular aspects of familial cancer syndromes that involve the skin. (J Am Acad Dermatol 2000;42:939–69.) Learning Objective: After completing this article, the reader should become (1) fluent with some basic genetic principles underlying the mechanisms of cancer predisposition and positional cloning and (2) aware of the recent breakthroughs in the identification of familial cancer syndrome disease genes.