VAV1 is a hematopoietic signal transducer that possesses a GDP/GTP nucleotide exchange factor (GEF) that is tightly regulated by tyrosine phosphorylation, along with adapter protein domains, such as SH2 and SH3. Research onVAV1has advanced over the years since its discovery as an in vitro activated oncogene in an NIH3T3 screen for oncogenes. Although the oncogenic form ofVAV1first identified in the screen has not been detected in human clinical tumors, its wild-type and mutant forms have been implicated in mammalian malignancies of various tissue origins, as well as those of the hematopoietic system. This review article addresses the activity of humanVAV1as an overexpressed or mutated gene and also describes the differences in the distribution ofVAV1mutations in the hematopoietic system and in other tissues. The knowledge accumulated thus far from GEMMs expressingVAV1is described, with the conclusion that GEMMs of both wild-typeVAV1and mutantVAV1do not form tumors, yet these will be generated when additional molecular insults, such as loss of p53 or KRAS mutation, occur.