Nephrotoxicity of calcineurin inhibitors and uncontrolled effector function of alloreactive T lymphocytes are main drivers of transplant dysfunctions. T lymphocytes either directly damage tissues or indirectly promote inflammation and antibody responses. Beside inhibitors of calcium-dependent pathways and anti-metabolites, modulators of T cell co-stimulation are elected pharmacological tools to enable interference with immune-mediated transplant dysfunctions. CD28 and CTLA-4 are major co-stimulatory and co-inhibitory cell surface signaling molecules interacting with CD80/86, known to be critically important for immune response of committed T cells and regulation. Initial "bench to beside" translation, two decades ago, resulted in the development of belatacept (CTLA4-Ig), a biologic inhibiting interaction of both CD28 and CTLA-4 with CD80/86. Despite proven effectiveness in inhibiting allo-immune responses, clinical use of belatacept in kidney transplantation revealed a substantially high incidence of acute, cell-mediated rejection. The etiology of « belatacept-resistant graft rejection » was allocated to elevated pretransplant frequencies of CD28+ memory T cells. Owing to different requirement in CD28 costimulatory and CTLA-4 co-inhibitory signals to control naïve and memory T cells, selective antagonists of CD28-CD80/86 interactions have been developed on the rationale that preservation of CTLA4-mediated regulatory mechanisms would result in a better control of alloreactivity and would represent a "Treg-compatible" immunosuppression. After the successful testing of selective CD28 antagonists in First In Human studies, this review delineates how this shift in paradigm performed in preclinical transplantation models and evaluates its clinical potential.