CD96 represents a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily. CD96 is expressed mainly by cells of hematopoietic origin, in particular on T and NK cells. Upon interaction with CD155 present on target cells, CD96 was found to inhibit mouse NK cells, and absence of this interaction either by blocking with antibody or knockout of CD96 showed profound beneficial effects in containment of tumors and metastatic spread in murine model systems. However, our knowledge regarding CD96 functions remains fragmentary. In this review, we will discuss structural features of CD96 and their putative impact on function as well as some unresolved issues such as a potential activation that may be conferred by human but not mouse CD96. This is of importance for translation into human cancer therapy. We will also address CD96 activities in the context of the immune regulatory network that consists of CD155, CD96, CD226, and TIGIT.