According to recent estimates, more than 70 million people have been infected with the human immunodeficiency virus (HIV) and millions of them have already died. The effect of HIV infection on individuals and communities is socially and economically devastating. Although the development of new antiviral drugs has had a dramatically beneficial impact on HIV-infected individuals with access to treatment, it has had negligible impact on the global epidemic. Similarly, a prophylactic or therapeutic HIV/AIDS vaccine remains on the highest priority in the world HIV/AIDS agenda. The generation of a vaccine against HIV/AIDS has turned out to be extremely challenging, as indicated by more than 25 years of unsuccessful attempts. The lack of our understanding of the basic virus-host interaction and of the associated pathogenetic mechanism(s) represent a major hurdle for the development of any intervention against HIV/AIDS. Here are reviewed the major problems in the field and are highlighted the key aspects on the virus-host interaction at the port of the entry.