Productive infection with HIV-1 is mediated by fusion of the HIV-1 envelope with the cell membrane and subsequent entry of the virion core into the cytoplasm. The core is then rearranged to form the reverse transcription complex which is responsible for conversion of the genomic RNA to its double-stranded DNA copy. Various genetic, biochemical and microscopy studies have shed light on the role of viral proteins in the core in this process; Gag cleavage products, in particular, are crucial. It is also at this point that core is potentially exposed to the action of restriction factors such as TRIM5α and APOBEC3G, highlighting the vulnerability of this stage of the retrovirus life-cycle to the cells defenses. Rearrangement of the core may be an active process involving host-cell activities, although this is not clear, but may also be partly passive due to the instability of the structure. What regulates this process is unknown. Several host-cell kinase activities are important for replication and have been shown to be incorporated in the virion. We speculate that these kinases may regulate core rearrangement or the interaction of the reverse transcription complex/pre-integration complex with the cytoplasm. Recent real-time microscopy experiments with fluorescent-labeled probes suggest a model in which the virion utilizes the cytoskeleton for transport whilst in the cytoplasm. After entering the cell, the virion interacts initially with actin filaments which assist binding to microtubles enabling transport to the nuclear periphery. An actin-transport process may then facilitate the remaining short journey to the nuclear membrane.