The primary goal of a virus is the infection of host cells so it can replicate its genome and so it can produce progeny virions for the infection of new target cells. Some viruses cause long-lasting chronic infections while others replicate in fast, lytic cycles. However, replication of all viruses depends to a large degree on specific host factors from the recognition of specific cell surface receptors required for virus entry into a target cell to the packaging of cellular factors into virions. HIV penetrates target cells through fusion with the host plasma membrane. Penetration is followed by partial uncoating and reverse transcription of the viral RNA and subsequent integration of the double-stranded cDNA into the host genome. The integrated provirus then serves as template for the synthesis of viral proteins, which ultimately assemble into progeny virions that are released from the infected host cell. We are far from understanding all of the complex virus-cell interactions that take place during a single replication cycle; however, our current knowledge on the replication of HIV suggests that such interactions occur at virtually every step during the course of virus replication. Recent years have brought rapid progress in the identification and characterization of novel host factors supporting HIV replication. In particular, the recent identification of host restriction factors such as Trim-5α or APOBEC3G as well as the identification of Bst-2/Tetherin as a target of Vpu has significantly advanced our understanding of HIV cell tropism. The molecular mechanisms that dictate host restrictions and govern virus-host interactions, however, remain poorly understood.