Active BK virus (BKV) infection in immunocompromised patients is associated with significant disease, most notably nephropathy in kidney transplant recipients and hemorrhagic cystitis in hematopoietic stem cell transplant recipients. Efforts to discover novel antivirals that inhibit BKV replication are challenging due to the lack of traditional antiviral targets (e.g., polymerases, proteases). Our group is focused on exploring different stages of the viral life cycle to identify new targets and possibilities for intervention. More specifically, despite several decades of active research, the precise route and mechanism of polyomavirus trafficking and delivery of the viral genome to the nucleus are unknown. A better understanding of the cellular and biochemical mechanisms associated with these stages of the viral life cycle may identify molecular opportunities to inhibit BKV replication. We also aim to learn more about host factors that play a key role in the viral life cycle to identify cellular proteins that could be targeted and have therapeutic potential as antivirals for BKV.