Drug repurposing is at the heart of precision oncology. The move from tissue- or cancer-specific treatments to genomic- or actionable-target treatments necessarily entails the reuse of anti-cancer medications licensed for one type of cancer to treat other cancer types. However, given the genetic heterogeneity of individual cancers, limiting the search of suitable agents to existing oncological drugs limits treatment options. It misses a wide range of possibly useful agents from other disease areas. If we characterize the re-use of existing oncological drugs to new indications as “soft repurposing,” then the use of non-cancer drugs as anti-cancer medications may be termed “hard repurposing” and poses a number of distinct challenges.