More than a decade has passed since the discovery that the peptidyl prolyl isomerase cyclophilin A (CypA) specifically binds to a proline-rich sequence in HIV-1 capsid (CA) and is thereby incorporated into viral particles. Since then, a variety of possible functions of CypA in the HIV-1 replication cycle have been intensively investigated, but the biological function of this interaction remains to be determined. The binding of CypA to CA increases HIV-1 infectivity in human cells, but promotes an anti-HIV-1 restriction activity in cells from nonhuman primates. Numerous studies have been undertaken to understand the paradoxical effects of CypA and, along with the parallel discovery of the restriction factor tripartite motif 5α, our understanding of how CypA modulates HIV-1 infectivity has now been changed completely. However, 13 years after its discovery, the biological function of the specific interaction between HIV-1 CA and CypA is still not fully understood. Even though much insight has been provided to date, many questions remain unanswered.