This chapter reviews the productive application of Toxoplasma as a model system for apicomplexan drug discovery, in particular for the validation of potential targets. The need for effective validation tools is driven by the plethora of potential targets revealed by systematic comparative analysis of completed genomes of Toxoplasma, Theileria, Plasmodium, Cryptosporidium, and Eimeria. However, the novelty alone of a gene or pathway in the genome of a pathogen compared with the host is not the only criterion for deeming a potential target an attractive one. Indeed, some well-established or novel antiparasitic targets are orthologs of enzymes present in the animal host, where subtle evolutionary divergence can be effectively exploited by selective small molecule inhibitors. Of fundamental importance to any discovery endeavor is genetic validation, the demonstration that a potential gene target is essential rather than functionally redundant or (unexpectedly) dispensable in nature. With a full complement of molecular tools available, molecular genetic interrogation of any gene of interest is now eminently feasible. The ease with which Toxoplasma can be cultivated both in vitro and in rodent models facilitates the evaluation of compounds with desirable efficacy and pharmacological properties.