Despite the development of drugs inhibiting the oncogenic proteins that cancer cells are dependent on, attempts to match targeted therapies to the genetic makeup of individual tumors is proving more difficult than expected. Until now, the paradigm has been a binary correlation between a mutated cancer gene and response to a given therapy. However, recent evidence indicates that different genetic alterations, such as mutations in different codons of a cancer gene, might be related to distinct sensitivity to targeted therapies. An example is the divergent effect that individual EGFR, PIK3CA and KRAS mutations might have on response or resistance to tailored drugs. Furthermore, the idea that the presence of a specific mutation translates into sensitivity or resistance to a particular drug is likely too simplistic, since it does not capture the complexity of the signaling pathways in an individual cancer. Only the overall genetic milieu (alterations in upstream and/or parallel pathways) ultimately determines the response of individual tumors to therapy. We have critically analyzed data supporting the genetic, biological and biochemical differences of individual mutations within a single cancer gene. The role of cancer mutations as predictors of sensitivity and resistance to targeted therapies is discussed, together with the implications for the 'personalized' treatment of cancer patients.