The Fhit protein is lost early in the development of many human cancers. Loss of Fhit in the mouse predisposes the organism to an array of tumors, including stomach and sebaceous carcinomas that resemble human Muir-Torre syndrome. Re-expression of Fhit in cancer cells unable to synthesize the protein induces apoptosis by an unknown mechanism. We have taken two orthogonal genomic approaches to identify additional proteins in the Fhit pathway. First, by cloning Fhit homologues from a wide variety of genomes, we discovered that Fhit is made as a natural fusion or Rosetta Stone protein in invertebrates. We will show phylogenetic profiles, expression analysis, and the crystal structure of the 200-kD NitFhit tetramer from worms to demonstrate that the fusion partners Nit and Fhit have a conserved interaction. Second, we have developed a new method by which an entire genome can be interrogated for synthetic genetic interactions. Synthetic lethals are a valuable means of finding interacting proteins because, beyond identifying the proteins in a pathway, the product of a gene that is synthetically lethal with loss of Fhit is arguably the best drug target for specific elimination of cancer cells unable to synthesize Fhit. We will demonstrate how we use array hybridization to conduct a genome-wide synthetic screen in yeast and give an example of a conserved kinase pathway that is synthetically lethal with mutations in a yeast histidine triad protein.