The use of mice to model human infectious disease is attractive given that the level of understanding immune function in mice is unparalleled. Development of a mouse model for HIV infection would additionally be useful in testing the efficacy of various drug protocols in vivo. However, murine cells are naturally refractory to HIV infection. The recent identification of human cofactors required for HIV entry and gene transcription has enabled circumvention of some restrictions present in murine cells. Mice transgenic for cofactors such as human CD4, CCR5, and cyclin T1 have been generated. In spite of these advancements, murine cells expressing the human cofactors are still several orders of magnitude less efficient than human cells in the production of infectious HIV. Characterization of these remaining restrictions in murine cells will aid in determining how to further manipulate the mouse and/or HIV-1 genome in order to obtain a viable murine model for HIV-1 infection.