In type 1 diabetes, insulin producing pancreatic β-cells are attacked and destroyed by autoreactive T cells, which causes major impairments of blood glucose metabolism and finally development of life-threatening complications. Currently, the treatment of this devastating disease is based on the substitution of insulin and thus can be considered palliative. Curative treatment approaches by contrast need to target the underlying causes of disease development: in this case, the autoreactive immune system and the loss of active β-cell mass. In recent years, several clinical trials have been performed studying the effects of diverse immunomodulating agents in order to halt the autoreactive immune response or finding paths to repopulate β-cell mass that could restore euglycemia. While some of the treatments showed remarkable outcomes, most of the studies failed to improve the course of disease. The reason might be that none of the candidates currently under investigation are potent enough at tolerable dosages to hold the key for the cure. Subsequently, the idea of combining defined substances has evolved in order to detect synergistic effects and improve the strength of the therapeutic potential. Observations from mouse models and clinical experience from various other diseases where combination therapies often constitute the standard treatment strongly support this hypothesis. Here, we discuss promising monotherapeutic approaches, summarize current clinical trials and propose a rationale on how to prioritize different combinations of treatments.