Inclusion of transmission-blocking agents in combination therapies for malaria could help eliminate the disease. Through a screen of compounds from the Novartis-GNF Malaria Box, Vanaerschot et al. identify hexahydroquinolines (HHQs) as potent Plasmodium falciparum (Pf) gametocyte (GAM) and asexual blood stage inhibitors. Transmission-blocking activity of HHQs was confirmed in in vitro assays using Pf GAMs and gametes. In Plasmodium berghei-infected mice, HHQs suppressed blood-stage parasite proliferation. In vitro HHQ resistance selection studies identified mutations in Pf multidrug resistance gene-1, which sensitized parasites to first-line antimalarial drugs.