To insure its survival, the human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), utilises more than one gate to enter a target cell. This strategy makes it more difficult for the immune system to defeat the virus. This has also made it difficult for scientists working in the HIV research to understand how exactly HIV infects a susceptible human cell. Such understanding will no doubt open many gates for scientists to vanquish the virus by designing agents that can block HIV entry into target cells, thus rendering the virus vulnerable to immune destruction. This will also help in understanding the replication of the virus and the pathogenesis of the disease. The present article briefly describes the past and current thinking of how HIV-1 infects a susceptible human cell, and the dilemma scientists are facing when studying the infectivity of this virus and applying current knowledge to design agents that can block HIVs entering target cells. In the context of our own experience with HIV infectivity in vitro, the present article will also address the behaviour of different HIV isolates, both laboratory-adopted and clinical (primary) isolates in culture and the difficulties in performing HIV infectivity testing. Moreover, our experience of peripheral blood mononuclear cells' (PBMCs) susceptibility to HIVs infection in vitro is discussed.