Diabetes mellitus is an incurable progressive disease, characterized by elevated blood glucose levels, which lead to the development of micro- and macrovascular complications. Although the etiopathology of the disease remains unclear, it seems to be multifactorial, with an important interaction between genetics and environmental causes. Currently, the genetics of type 2 diabetes (T2D) is poorly understood. The recent advance of the genetic technologies and with a better understanding of genetics, more than 120 distinct genetic loci, with more than 150 variants, have been identified that may be involved in the pathogenesis of T2D. However, as these variants can account for only approximately 20% of the heritability of T2D, there is an obvious need for additional approaches to identify susceptibility genes or genetic mechanisms involved in the development of this disease. There is a growing number of genes found to be related to T2D; however, their individual impact on the pathogenesis of the disease appears to be low, while silencing of protective genes may also contribute to the development of this disease. The present review attempts to summarize our current knowledge in the field of genetics of T2D, highlighting the possible practical applications for each approach.