Thiazolidinedione (TZD), a class of drugs that are mainly used to control type 2 diabetes mellitus (T2DM), acts fundamentally as a ligand of peroxisome proliferator-activated receptors (PPARs). Besides activating pathways responsible for glycemic control by enhancing insulin sensitivity and lipid homeostasis, activating PPARs leads to exciting other pathways related to bone formation, inflammation, and cell proliferation. Unfortunately, this diverse effect of activating several pathways may show in some studies adverse health outcomes as osteological, hepatic, cardiovascular, and carcinogenic effects. Thus, a silver demand is present to find and develop new active and potent antiglycemic drugs for treating T2DM. To achieve this goal, the structure of TZD for research is considered a leading structure domain. This review will guide future research in the design of novel TZD derivatives by highlighting the general modifications conducted on the structure component of TZD scaffold affecting their potency, binding efficacy, and selectivity for the control of T2DM.