Fifteen years ago Lee Hartwell, Stephan Friend and colleagues published a classic paper suggesting that synthetic lethal approaches in yeast and other model organisms could by applied profitably to the identification of genotype-selective anticancer agents. This concept has been immensely influential in the field and upon my own work at the University of Toronto and at Columbia. But...has the potential of this approach been realized as far as developing successful new therapies for treating cancer? We get an update on progress made so far (spoiler: not much) and directions for future work in Science.