Parasitic diseases caused by protozoan pathogens lead to hundreds of thousands of deaths per year in addition to substantial suffering and socioeconomic decline for millions of people worldwide. The lack of effective vaccines coupled with the widespread emergence of drug‐resistant parasites necessitates that the research community take an active role in understanding host–parasite infection biology in order to develop improved therapeutics. Recent advances in next‐generation sequencing and the rapid development of publicly accessible genomic databases for many human pathogens have facilitated the application of systems biology to the study of host–parasite interactions. Over the past decade, these technologies have led to the discovery of many important biological processes governing parasitic disease. The integration and interpretation of high‐throughput ‐omic data will undoubtedly generate extraordinary insight into host–parasite interaction networks essential to navigate the intricacies of these complex systems. As systems analysis continues to build the foundation for our understanding of host–parasite biology, this will provide the framework necessary to drive drug discovery research forward and accelerate the development of new antiparasitic therapies. WIREs Syst Biol Med 2015, 7:381–400. doi: 10.1002/wsbm.1311This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease Models of Systems Properties and Processes > Organismal Models Biological Mechanisms > Regulatory Biology