<p>Context-dependent synthetic lethality offers a promising strategy for expanding the scope of precision oncology beyond direct oncogene inhibition. We describe various genetic contexts that produce cancer-intrinsic vulnerabilities and consequent synthetic lethal opportunities. We also identify common mechanistic themes that underlie synthetic lethality, such as DNA repair defects, loss of functional redundancies, metabolic imbalances and narrow signalling tolerances. Whereas clinical translation has seen success — for example, with inhibitors of poly(ADP-ribose) polymerase (PARP), hypoxia-inducible factor 2 (HIF-2) and Smoothened (SMO), other targets require more nuanced strategies to achieve selectivity. Case studies highlight that therapeutic index, often inferable from functional genomics, is a critical determinant of success and should guide both target prioritization and therapeutic strategy. They also reveal that specific molecular mechanisms underlying the synthetic lethal phenotype can inform the discovery of the optimal therapeutic modality. Finally, we describe emerging approaches for synthetic lethal target discovery and drug development that enable diverse therapeutic strategies. Together, these insights provide a framework for translating synthetic lethality into more selective and durable cancer therapies.</p>