Susceptibility to HIV infection and the modulation of disease progression are strictly dependent on inter-individual variability, much of which is secondary to host genetic heterogeneity. The study of host factors that control these phenomena relies not only on candidate gene approaches but also on unbiased genome-wide genetic and functional analyses. Additional new insights stem from the study of mechanisms that control the expression of host and viral genes, such as miRNA. The genetic host factors that have been suggested to be associated either with resistance to HIV-1 infection or with absent/delayed progression to AIDS are nevertheless unable to fully justify the phenomenon of differential susceptibility to HIV. Multidisciplinary approaches are needed to further analyze individuals who deviate from the expected response to HIV exposure/infection. Results of these analyses will facilitate the identification of novel targets that could be exploited in the setting up of innovative therapeutic or vaccine approaches.