The genomics revolution has provided an overwhelming choice of potential drug targets for cancer therapy. Central to this revolution are approaches that identify target genes by changes in gene expression or through bioinformatic searching of DNA / protein databases for homologous sequences. An alternative to these approaches is functional cloning which selects gene products based on the ability of a given sequence to directly alter a cellular phenotype of interest. In an effort to discover new cancer therapeutic targets, bioinformatic searching and functional cloning were utilized to identify novel gene products implicated in various aspects of tumorigenesis. Using homology searches of DNA databases for novel death domain-encoding expressed sequence tags (ESTs), a new member of the TNF receptor family, DR6, was identified that regulated apoptosis in a variety of cell types and exhibited deregulated expression in tumor cells. Functional cloning of cDNAs from tumor cells with the capacity to induce morphological transformation, uncovered a unique oncogene, FGFR2-FRAG1, that resulted from a chromosomal rearrangemen t between a receptor tyrosine kinase, FGFR2, and a novel gene, FRAG1. This review focuses on these approaches as a means to identify potential targets for therapeutic intervention in cancer and the unique challenges each of these techniques face to link the identified gene products to a given biological effect or disease state.