Recent advances in immunology and a growing arsenal of new drugs are bringing the focus of tolerance research from animal models into the clinical setting. The conceptual framework for therapeutic tolerance induction has shifted from a "sledgehammer" approach that relies solely on cellular depletion and cytokine targeting, to a strategy directed toward restoring a functional balance across the immune system, namely the different populations of naive cells, effector and memory cells, and regulatory cells. Unlocking the key to tolerance induction in the future will likely depend on our ability to harness the functions of T regulatory cells. Also, dendritic cells are strategically positioned at the interface between innate and adaptive immunity and may be subject to deliberate medical intervention in a way that can control a chronic inflammatory response. Many reagents with tolerance-inducing potential are currently undergoing clinical testing in transplantation, autoimmune diseases, and allergic diseases, and even more that are on the horizon promise to offer enormous benefits to human health.