Retroviruses are relevant human pathogens affecting the lives of tens of millions of people globally each year and resulting in nearly 2 million deaths annually. Understanding the process of retrovirus infection has wide benefits including the identification of therapeutic targets to treat HIV/AIDS and better understanding of cellular pathways disrupted in diseases, such as cancer and AIDS. Here, I first present my role in a collaborative project that led to the identification of over 200 cellular factors with potentially important roles in the early stages of retrovirus infection. We identified these factors through a genome-wide siRNA screen and through characterization of interactions between host and virus proteins. Additionally, I present my work on ZASC1, a host cell transcription factor that binds to the promoter regions of both HIV-1 and MLV and regulates virus gene expression in cultured established cell lines. I generated a ZASC1 knockout mouse model, showing that this gene is non-essential to development and reproduction. This mouse model was used to characterize the role of ZASC1 in retrovirus replication and disease pathogenesis. I showed that ZASC1 influences myeloid cell differentiation in this compartment and that this transcription factor is required for efficient early Mo-MuLV infection in the bone marrow compartment. Through studies of Mo-MuLV pathogenesis in the ZASC1 knockout mouse model, I show that despite this early defect, tumorigenesis is not regulated by ZASC1.