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In recent years, the list of tumor suppressor genes (or candidate TSG) that are inactivated frequently by epigenetic events rather than classic mutation/deletion events has been growing. Unlike mutational inactivation, methylation is reversible and demethylating agents and inhibitors of histone deacetylases are being used in clinical trails. Highly sensitive and quantitative assays have been developed to assess methylation in tumor samples, early lesions, and bodily fluids. Hence, gene silencing by promoter hypermethylation has potential clinical benefits in early cancer diagnosis, prognosis, treatment, and prevention. The hunt for a TSG located at 3p21.3 resulted in the identification of the RAS-association domain family 1, isoform A gene (RASSF1A). RASSF1A falls into the category of genes frequently inactivated by methylation rather than mutational events. This gene is silenced and frequently inactivated by promoter region hypermethylation in many adult and childhood cancers, including lung, breast, kidney, gastric, bladder, neuroblastoma, medulloblastoma, gliomas and it has homology to a mammalian Ras effector (i.e., Nore1). RASSF1A inhibits tumor growth in both in vitro and in vivo systems, further supporting its role as a TSG. We and others identified the gene in 2000, but already there are over a 150 publications demonstrating RASSF1A methylation in a large number of human cancers. Many laboratories including ours are actively investigating the biology of this novel protein family. Thus far, it has been shown to play important roles in cell cycle regulation, apoptosis, and microtubule stability. This review summarizes our current knowledge on genetic, epigenetic, and functional analysis of RASSF1A tumor suppressor gene and its homologues.