A hallmark of the retroviral replication cycle is the catalytic integration of viral DNA (vDNA) into host chromatin, which leads to the establishment of a permanent infection in the target cell. Integration is mediated by a large nucleoprotein assembly called an intasome, composed of retroviral integrase (IN) and vDNA. Intasomes preferentially target nucleosomes for catalytic integration of vDNA into host DNA. Further, intasomes, but not free IN, are targeted by some of the latest antiretroviral therapeutics, called IN strand transfer inhibitors (INSTIs), which are used in the clinic to treat HIV-infected individuals. I will discuss our latest progress toward understanding the molecular basis for intasome-mediated retroviral integration into host chromatin using cryo-EM structural biology. I will also discuss some of the latest developments in defining the distinct modes of INSTI binding to intasomes and early efforts toward understanding mechanisms of viral escape against INSTI use, as well as therapeutic strategies to combat resistance.