The combination of medicinal chemistry and model-organism genetics is emerging as a powerful tool for the discovery and validation of drug targets. Model systems can be used to identify the cognate target for compounds that demonstrate in vivo efficacy but have unknown mechanisms of action. Alternatively, drugs with known cognate targets can be used to probe biochemical pathways in model organisms, revealing new targets and mechanisms within these pathways. In both cases, the availability of human genomic sequence data is opening up new opportunities for accelerating target discovery.