The acquired immunodeficiency syndrome (AIDS) emerged in the human population in the summer of 1981. According to the latest United Nations estimates, worldwide over 33 million people are infected with human immunodeficiency virus (HIV) and the prevalence rates continue to rise globally. To control the alarming spread of HIV, an urgent need exists for developing a safe and effective vaccine that prevents individuals from becoming infected or progressing to disease. To be effective, an HIV/AIDS vaccine should induce broad and long-lasting humoral and cellular immune responses, at both mucosal and systemic level. However, the nature of protective immune responses remains largely elusive and this represents one of the major roadblocks preventing the development of an effective vaccine. Here we summarize our present understanding of the factors responsible for resistance to infection or control of progression to disease in human and monkey that may be relevant to vaccine development and briefly review recent approaches which are currently being tested in clinical trials. Finally, the rationale and the current status of novel strategies based on nonstructural HIV-1 proteins, such as Tat, Nef and Rev, used alone or in combination with modified structural HIV-1 Env proteins are discussed.