Owing to the absence of antiparasitic vaccines and the constant threat of drug resistance, the development of novel antiparasitic chemotherapies remains of major importance for disease control. A better understanding of drug transport (uptake and efflux), drug metabolism and the identification of drug targets, and mechanisms of drug resistance would facilitate the development of more effective therapies. Here, we focus on malaria and African trypanosomiasis. We review existing drugs and drug development, emphasizing high-throughput genomic and genetic approaches, which hold great promise for elucidating antiparasitic mechanisms. We describe the approaches and technologies that have been influential for each parasite and develop new ideas for future research directions, including mode-of-action studies for drug target deconvolution.