Proglucagon-derived peptides represent a class of peptide hormones derived from the proglucagon precursor. These peptides, including glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), and oxyntomodulin, exert diverse effects on several aspects of human physiology, ranging from glucose, lipid, and protein metabolism to appetite regulation, nutrient absorption, and gastrointestinal motility. Their actions are mediated by distinct G protein-coupled receptors, influencing endocrine, neuroendocrine, and metabolic processes, and over recent decades the proglucagon-derived peptides have emerged as central players in the management of metabolic and gastrointestinal diseases. Glucagon has long been recognized for its role in treating hypoglycemia, whereas GLP-1 receptor agonists have revolutionized the treatment of type 2 diabetes and obesity because of their glucose-lowering, appetite-suppressing, and cardiovascular protective effects. GLP-2 analogs offer targeted therapy for short bowel syndrome, addressing critical needs in this nutrient malabsorptive condition. This clinical review provides an exploration of the human physiology of the proglucagon-derived peptides, their involvement in pathophysiology, and their therapeutic applications. We discuss advancements in mono- and multireceptor agonists from a clinical perspective that leverage combined actions and explore future perspectives, including novel indications.