We report a concise and convergent laboratory synthesis of the rare marine natural product lehualide B that has led to the discovery that (1) this compound has low nanomolar activity against human multiple myeloma cells and (2) the anticancer effects of lehualide B and its analogues are selective (i.e., they are approximately 2-3 orders of magnitude less toxic to human breast cancer cells). Synthetic lehualide B is shown to be an effective inhibitor of complex I of the mitochondrial electron transport chain, with potency similar to that observed for the terrestrial natural products piericidin A1 and rotenone, an observation that led to the discovery that piericidin A1 is also selectively cytotoxic toward human multiple myeloma cells. Interestingly, synthetic derivatives of lehualide B that resemble verticipyrone (an established complex I inhibitor composed of a γ-pyrone and a simple monounsaturated hydrophobic chain) lack the potent antimyeloma activity of the natural product. Finally, the synthesis and evaluation of a collection of lehualide-inspired analogues led to the elucidation of structure-activity relationships for this rare natural product that established important roles for the substituted γ-pyrone headgroup and the skipped polyene side chain.