Human monogenic diseases are the best “animal models” of genetic alterations made by nature. Studying these diseases offers precious pathways to the understanding of basic biology and formulation of precision medicine even today. Diabetes mellitus (DM) is a heterogeneous disorder manifested with hyperglycemia. The genetic spectrum ranges from monogenic to complex disease. The clinical features of monogenic DM are early onset of age, relatively normal body mass index and strong indication of Mendelian autosomal dominant inheritance in family. Using next generation whole exome sequencing provides a very effective way to decipher the genetic diagnosis for these families and their pathophysiology.