Intensive research for 50 years did not find a way to predict the faith of organ transplants after successful transplantation. Current immunosuppressive regiments reduce kidney transplant acute rejection episodes to 6–11% for the first year, but 49% of them develop chronic allograft nephropathy in 5 years. Similarly, heart transplants have 8% acute rejection episodes in the first year and 50% develop cardiac vasculopathy in 5 years. Multiple cytokines regulate acute cellular T-cell-mediated rejection (TCMR) and acute antibody-mediated rejection (AMR), and both mechanisms contribute to chronic allograft rejection. In addition to common γ chain (cγ) cytokines [interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21], other cytokines [IL-1, IL-6, IL-10, interferon-α, (IFN)α, INFβ, INFγ, tumor necrosis factor α, TNFα; tumor growth factor β, TGFβ] are all extensively involved in the regulation of acute and chronic allograft rejections. Interestingly, the same cytokines also regulate functions of normal cells and tissues. To induce transplant tolerance, it is necessary to maintain physiological cytokine levels as well as boost the function of T regulatory T (Treg) cells producing IL-10, IL-35, and TGFβ. This chapter emphasizes the necessity of maintaining a balance by cytokines to divert them from the inflammation path producing chronic rejection to normal function support combined with Treg-dominated transplantation tolerance.