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Issue 285: A drug combination that works better than expected from the efficacy of the individual drugs seems like it should be all upside and no downside, and indeed, this combinational synergy has been the motivation for many drug combinations. However, recent computational and experimental work on combination therapies in Acute Myeloid Leukemia, demonstrated that this synergy has an unintended consequence – increased development of resistance. A commentary of this work likens synergy to siren songs from Greek mythology, luring us towards seemingly promising combinations that result in increased resistance. A theoretical model, supported by extensive experimental evidence, demonstrates that synergy increases the impact of resistance to one drug since both the effect of that drug and the added benefit of synergistic interaction are lost. This result suggests that, when designing combinations, the lure of the siren song of synergy should be resisted to avoid increased drug resistance.