OBJECTIVE： To investigate the relationship of the function and gene polymorphism of insulin receptor substrate （IRS） with type 2 diabetes mellitus （T2DM）， and to provide a new perspective for T2DM drug development. METHODS： Relevant literatures included in CNKI， Wanfang， VIP， PubMed， SpringerLink and other databases from Jan. 1991 to Nov. 2017 were retrieved by using “Insulin receptor substrate” “Type 2 diabetes” “Insulin resistance” “Polymorphism” as Chinese keywords， and “Insulin receptor substrate” “IRS” “Type 2 diabetes” “Insulin resistance” “Polymorphism” as English keywords. The relationship of the function and gene polymorphism of IRS family with T2DM was reviewed. RESULTS & CONCLUSIONS： A total of 328 literatures were retrieved， of which there were 38 valid literatures. At present， IRS family has six members （IRS-1 to IRS-6）. The dysfunction of IRS-1 and IRS-2 will lead to insulin resistance and induce T2DM. The relationship of IRS-3 and IRS-4 with T2DM remains controversial. IRS-5 and IRS-6 were newly found and their functions are not clear. The Gly972Arg mutation of IRS-1 is positively correlated with the pathogenesis of T2DM. Gly1057Asp mutation of IRS-2 combined with obesity can induce insulin resistance， but there is controversy. The mutation types of IRS family other members include Ala94Thr， Ala512Pro and Ser892Gly mutation of IRS-1， ACC， Ala157Thr and Leu647Val mutation of IRS-2. The relationship between these types of mutation and T2DM has not yet been fully supported. Multiracial and large-scale studies are required. Some achievements have been made in the present study， but the study is not yet comprehensive. Relationship of IRS family members and their mutation sites with T2DM still needs to be further tested in the expanded population.