For over a century, heme metabolism has been recognized to play a central role during intraerythrocytic infection by parasites, the causative agent of malaria. Parasites liberate vast quantities of potentially cytotoxic heme as a by-product of hemoglobin catabolism within the digestive vacuole, where heme is predominantly sequestered as inert crystalline hemozoin. spp. also utilize heme as a metabolic cofactor. Despite access to abundant host-derived heme, parasites paradoxically maintain a biosynthetic pathway. This pathway has been assumed to produce the heme incorporated into mitochondrial cytochromes that support electron transport. In this review, we assess our current understanding of the love-hate relationship between parasites and heme, we discuss recent studies that clarify several long-standing riddles about heme production and utilization by parasites, and we consider remaining challenges and opportunities for understanding and targeting heme metabolism within parasites.

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