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Infection with Human immunodeficiency virus type-1 (HIV-1) induces severe alterations of the immune system leading to an increased susceptibility to opportunistic infections and malignancies. However, exposure to the virus does not always results in infection. Indeed, there exist individuals who have been repeatedly exposed to HIV-1 but do not exhibit clinical or serological evidence of infection, known as exposed seronegative individuals. Many studies have focused on the different mechanisms involved in natural resistance to HIV-1 infection, and have reported several factors associated with this phenomenon, including the presence of genetic polymorphisms in the viral coreceptors, innate and adaptive immune cells with particular phenotypic and functional features, and molecules such as antibodies and soluble factors that play an important role in defense against infection by HIV-1. The study of these factors could be the key for controlling this viral infection. This review summarizes the main mechanisms involved in resistance to HIV-1 infection.