CD28 was identified in early 1980s by Martin and colleagues by monoclonal antibodies recognizing a 44 kDa protein on the surface of human T lymphocytes (Martin et al. 1980). Further experiments from Gmunder and Lessener evidenced the crucial role of this molecule in costimulating T cell responses by synergizing with PHA in inducing T cell proliferation (Gmunder and Lesslauer 1984). Later in 1987, Aruffo and Seed cloned the cDNA of human CD28 and showed that it encodes for a 23 kDa glycosylated type I transmembrane protein expressed as disulfide-linked homodimer on the surface of 80 % of human CD4+ T cells, 50 % of human CD8+ T cells (Aruffo and Seed 1987). In mouse, CD28 was cloned in 1990 by Gross and colleagues and found expressed on 100 % of both CD4+ and CD8+ T cells (Gross et al. 1990). In the same years, the natural ligands of CD28 were also identified. In 1989, Freeman and colleagues identified B7.1 also known as CD80 on the surface of activated B lymphocytes (Freeman et al. 1989) that further studies from Azuma and colleagues demonstrated to bind to CD28 (Azuma et al. 1993). Later, the same group also cloned and identified B7.2 or CD86 as a CD28 binding partner (Freeman et al. 1993). Since its discovery, it has becoming clear that CD28 was the most prominent co-stimulatory molecule able to deliver the signal two necessary for full T lymphocyte activation. The two signal model of T lymphocyte activation predicts that optimal T cell response to antigen is achieved following the recognition of peptide-major histocompatibility complex (MHC) by TCR (signal one) together with a subset of co-stimuli (signal two), generally provided by counter-receptors expressed on the surface of APCs. Extensive in vitro and animal model studies demonstrated that CD28 delivers signals that complement TCR in both qualitative and quantitative manners, thus promoting/enhancing cell proliferation, high levels of cytokines, cell survival and T cell differentiation. More recent studies also evidenced the ability of CD28 to function in a TCR independent manner (Porciello and Tuosto 2016).