The retrovirus family contains several important human and animal pathogens, including the human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS). Studies with retroviruses were instrumental to our present understanding of the cellular entry of enveloped viruses in general. For instance, studies with alpharetroviruses defined receptor engagement, as opposed to low pH, as a trigger for the envelope protein-driven membrane fusion. The insights into the retroviral entry process allowed the generation of a new class of antivirals, entry inhibitors, and these therapeutics are at present used for treatment of HIV/AIDS. In this chapter, we will summarize key concepts established for entry of avian sarcoma and leukosis virus (ASLV), a widely used model system for retroviral entry. We will then review how foamy virus and HIV, primate- and human retroviruses, enter target cells, and how the interaction of the viral and cellular factors involved in the cellular entry of these viruses impacts viral tropism, pathogenesis and approaches to therapy and vaccine development.