Drug resistance represents a major limitation to the long‐term efficacy of anti‐cancer treatments. The commonly accepted view is that the selection of inheritable genetic mechanisms governs the development of secondary resistance. However, compelling evidence suggests an important role for adaptive cell plasticity and non‐genetic mechanisms in the development of therapy resistance. The two phenomena are not mutually exclusive and the interplay between genetic and non‐genetic mechanisms may affect tumor evolution during treatment. A broader characterization of the genetic and non‐genetic mechanisms of drug resistance may pave the way for more precise and effective therapeutic strategies to overcome resistance.