Despite significant progress in recent decades, parasitic diseases remain among the principal causes of mortality and morbidity worldwide. Malaria parasites and helminths alone are responsible for more than half a billion clinical infections every year, with half of the world’s population at risk. Here, we propose experiments aimed at using state-of-the-art genomic technologies to address the impact of external factors on parasite development and disease outcome, with an emphasis on the influence of co-infection and host sex. While co- infections with multiple parasites are common, the consequences of poly-parasitism on disease transmission and outcomes remain poorly understood. We will use single-cell gene expression analyses to examine how drug treatment, as well as co-infections with multiple Plasmodium parasites, influence parasite transmission from hosts to mosquitoes, using a non-human primate model. Using a combination of genomics and transcriptomics methods, we will characterize the effect of ongoing Schistosoma haematobium infection on the host immune response to malaria infection in children, investigate if the immunomodulation exerted by schistosomiasis is long-lasting, and determine whether it impacts the genotype of the infecting malaria parasites. Finally, we will use an animal model to investigate the impact of host sex and site of infection on the development of filarial nematodes, and its putative consequences on differential drug efficacy in host males and females. These multi-disciplinary studies represent an initial step in the quantitative characterization of the role of co-infection on the outcome of parasitic infections, and in the investigation of host sex biases in parasitic infection studies. These two topics are critically understudied and yet impact millions of people worldwide. The implications of these findings could be wide-ranging, and include novel approaches to study parasitic infection and co-infections in human and animal models, as well as public health insights into immunization and treatment approaches in high-priority parasitic diseases.