The HIV surface glycoprotein, gp120, contains conserved and functional domains that exist within a viral envelope spike that is otherwise highly variable with respect to conformation, sequence and structure. Termed CD4-induced epitopes, these domains are stabilized on transition state gp120 structures as a consequence of CD4 receptor engagement. These nuggets of conservation naturally attract the attention of those seeking to develop vaccine and therapeutic strategies to fight infection by diverse HIV strains. However, an appreciation for the immunological relevance and practical value of CD4-induced epitopes is still evolving. This review covers the current findings related to the accessibility, antigenicity and immunogenicity of CD4-induced epitopes on gp120.