Modern medicine continues to evolve, and the treatment armamentarium for various diseases grows more individualized across a breadth of medical disciplines. Cure rates for infectious diseases that were previously pan-fatal approach 100% because of the identification of the specific pathogen(s) involved and the use of appropriate combinations of drugs, where needed, to completely extinguish infection and hence prevent emergence of resistant strains. Similarly, with the assistance of technologies such as next-generation sequencing and immunomic analysis as part of the contemporary oncology armory, therapies can be tailored to each tumor. Importantly, molecular interrogation has revealed that metastatic cancers are distinct from each other and complex. Therefore, it is conceivable that rational personalized drug combinations will be needed to eradicate cancers, and eradication will be necessary to mitigate clonal evolution and resistance. • Metastatic cancer complexity and heterogeneity requires moving beyond scripted monotherapies to tailored combinations. • Cancer may be akin to the mythical Hydra, whose nine heads must be all severed, as two heads grow back if one is slayed. • Patterns of response and resistance, such as mixed responses, provide clues to underlying molecular heterogeneity. • Customized (N-of-1) combination therapy may hold the key to killing the cancer hydra. [ABSTRACT FROM AUTHOR]