The malaria parasite has co-evolved with its human host as each organism struggles for resources and survival. The scars of this war are carried in the human genome in the form of polymorphisms that confer innate resistance to malaria. Clinical, epidemiological and genome-wide association studies have identified multiple polymorphisms in red blood cell (RBC) proteins that attenuate malaria pathogenesis. These include well-known polymorphisms in haemoglobin, intracellular enzymes, RBC channels, RBC surface markers, and proteins impacting the RBC cytoskeleton and RBC morphology. A better understanding of how changes in RBC physiology impact malaria pathogenesis may uncover new strategies to combat the disease.