c-Met and RON are receptor tyrosine kinases (RTK) that are closely related, both from a homology as well as from a functional stand point. Both receptors can induce cell migration, invasion, proliferation and survival in response to their respective ligand. Moreover, both possess oncogenic activity in vitro, in animal models in vivo and are often deregulated in human cancers. c-Met attracted a lot of interest shortly after its discovery in the mid-1980s because of its unusual role in cell motility. Moreover, a causal role for c-Met activating mutations in human cancer propelled an intensive drug discovery effort throughout the research and pharmaceutical communities to find inhibitors of c-Met. While c-Met is now a well-accepted target for an anti-cancer drug, less is known about the role of RON in cancer. Interestingly, despite their many common attributes, c-Met and RON are activated by different mechanisms in cancer cells. Because of the homology between the two RTKs, some small molecule kinase inhibitors of c-Met have inhibitory activity on RON, opening the door to exploring the role of both receptors in human cancers. In this review we will discuss the relevance of both c-Met and RON deregulation in human cancers and the progress so far in identifying small molecule kinase inhibitors that can block the activity of these targets in vitro and lead to anti-tumor effects in animal models.