MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that have critical regulatory functions in various biological processes. MicroRNA-22 (miR-22) is a highly-conserved 22-nt miRNA, whose roles in human diseases and normal physiology are just beginning to emerge. Recently, miR-22 has been connected to a great number of activities that encompass tumorigenesis, epigenetic modification, embryonic development, skeletal metabolism, panic disorder, and cardiomyocyte hypertrophy. Aberrant expression of miR-22 has been identified in multiple human diseases. Here, we describe our current understanding of the roles of miR-22 and its signaling circuitry in pathology and physiology, and discuss important advances that set the scene for applying miR-22 to the prevention and treatment of a wide range of human diseases.