Type 1A (immune-mediated) and type 2 diabetes mellitus are two of the most common severe chronic illnesses, affecting over 230 million people worldwide with an estimated global prevalence of 5.1%. Although type 1 and type 2 diabetes differ greatly in modes of pathogenesis, these illnesses share a common pathology and consequences characterized by loss of functional beta-cell mass and subsequent dysregulation of carbohydrate and lipid metabolism. Since therapy for diabetes and the associated complications poses enormous public health and economic burdens, novel preventive and regenerative therapies have emerged in the past decade with the aim to preserve beta-cell mass and delay the onset of diabetes. The goal of this review is to provide a comprehensive overview of current efforts in the fight against diabetes, and attempts to document all strategies that have emerged in clinical studies within the past 25 years. First, strategies to identify individuals at risk, ranging from whole-genome scans to autoantibody screening, will be discussed. Second, novel approaches to prevent or delay the onset of disease will be covered. Particular focus is given on emerging strategies for individuals at risk for type 1 diabetes that target T-cell regulation and induction of tolerance, while new pharmaceutical concepts in combination with lifestyle interventions are discussed within the scope of type 2 diabetes prevention. Lastly, important efforts to halt disease progression with emphasis on beta-cell regeneration are presented.