RAS genes are commonly mutated in human cancer, which is well established to initiate and promote tumorigenesis. Despite there being over 50 possible such ‘oncogenic’ mutations in these genes, each cancer type has a tropism towards a specific and often unique subset of these mutations. As RAS mutations typically occur early during tumorigenesis, if not being the initiating mutation, these mutational patterns ostensibly reflect fundamental biology underlying the process of tumor initiation. Thus, elucidating the mechanisms behind RAS mutation tropism will provide insight into one of the most foundational questions in cancer biology – how cancer originates – which has predictive and even preventative clinical implications.