Terminal and benign diseases alike in adults, children, pregnant women, and others are successfully treated by pharmacological inhibitors that target human enzymes. Despite extensive global efforts to fight malaria, the disease continues to be a massive worldwide health burden, and new interventional strategies are needed. Current drugs and vector control strategies have contributed to the reduction in malaria deaths over the past 10 years, but progress toward eradication has waned in recent years. Resistance to antimalarial drugs is a substantial and growing problem. Moreover, targeting dormant forms of the malaria parasite Plasmodium vivax is only possible with two approved drugs, which are both contraindicated for individuals with glucose-6-phosphate dehydrogenase deficiency and in pregnant women. Plasmodium parasites are obligate intracellular parasites and thus have specific and absolute requirements of their hosts. Growing evidence has described these host necessities, paving the way for opportunities to pharmacologically target host factors to eliminate Plasmodium infection. Here, we describe progress in malaria research and adjacent fields and discuss key challenges that remain in implementing host-directed therapy against malaria.