Introduction: In spite of significant efforts to reduce malaria deaths, this disease still kills around 445,000 people every year. Overcoming drug resistance is one of the main goals of current malaria research programs. This is challenging, since the biology of Plasmodium is not fully understood, requiring the development of advanced models for data analysis in the search for new antimalarials. Areas covered: In this review the authors introduce the importance of computational models to address the challenges of drug discovery, presenting examples of pioneering systems biology approaches in the search for new antimalarial drugs and their role in the future of drug research programs. Other related topics are discussed, e.g. regulation of malaria pathogenesis by epigenetics and the importance of new platforms for malaria network. Expert opinion: The use of a systems biology approach in antimalarial drug discovery emerges in a scenario where the most efficient antimalarial chemotherapies are showing resistance in Southeast Asia. New models for a better understanding of Plasmodium cell function have already proved to be powerful tools for uncovering complex mechanisms of resistance, and have great potential to inform the design of novel small molecules with both high antimalarial activity and transmission-blocking potential to improve the control of malaria.