Nitrogen-containing bisphosphonates, drugs used to treat bone resorption diseases, also have activity against a broad range of protists, including blood-stage Plasmodium spp. Here, we show that new-generation "lipophilic" bisphosphonates designed as anticancer agents that block protein prenylation also have potent activity against Plasmodium liver stages, with a high (>100) therapeutic index. Treatment of mice with the bisphosphonate BPH-715 and challenge with Plasmodium berghei sporozoites revealed complete protection (no blood-stage parasites after 28 days). There was also activity against blood-stage forms in vitro and a 4-day delay in the prepatent period in vivo. The lipophilic bisphosphonates have activity against a Plasmodium geranylgeranyl diphosphate synthase (GGPPS), as well as low nM activity against human farnesyl and geranylgeranyl diphosphate synthases. The most active inhibitor in vitro and in vivo had enzyme inhibitory activity similar to that of the other, less active compounds but was more lipophilic. Lipophilic bisphosphonates are thus promising leads for novel antimalarials that target liver-stage infection.