The HIV-1 matrix protein p17 (p17) plays a crucial role in the virus life cycle. It is released in the extracellular space from HIV-1-infected cells and accumulates in the tissues of patients, even in those successfully treated with highly active antiretroviral therapy. Extracellular p17 deregulates the biological functions of many different cells that are directly or indirectly implicated in AIDS pathogenesis. All p17 actions depend on interaction between its functional epitope (AT20), located at the protein N-terminal region, and different receptors expressed on target cells. This finding corroborates the importance of impeding p17/p17 receptors interaction as a contribution to block AIDS. In this article we review the interaction of p17 with heparan sulfate proteoglycans (HSPGs) and with the chemokine (C-X-C motif) receptor 1 (CXCR1) and 2 (CXCR2). We provide details on how p17 interacts with its receptors and how these interactions are central to the p17 biological activities. Moreover, we highlight the existence of a p17 variant, named S75X, which displays opposite effects on B-cell proliferation as compared to p17. A two-site model for p17 interaction with G-coupled receptors provides a possible explanation on how mutations naturally occurring within the primary amino acid structure can lead S75X to activate the Akt signaling pathway and to promote B-cell growth and transformation. Identification of p17 interaction with HSPGs, CXCR1 and CXCR2 as a fundamental event in supporting its activity could help to find new treatment approaches aimed at blocking all p17/p17 receptors interactions and, consequently, p17 detrimental activities.