Diabetic kidney disease (DKD) is a serious diabetic complication, the morbidity and mortality of which has rapidly increased worldwide. As known, the pathogenesis of DKD is complex and includes mesangial cell (MC) proliferation and hypertrophy, mesangial expansion, glomerular basement membrane thickening, podocyte detachment, and tubulointerstitial damage. Thus, the role of MCs cannot be underestimated, as their exclusive positioning and diverse physiological functions are crucial for preserving the glomerular filtration membrane's composition and functionality. Considerable animal studies and clinical trials have elaborated that MCs are pivotal to the occurrence and progression of DKD. In this review, we summarize and outline the mechanisms of MC injury and the interactions of MCs with other cells and discuss the progress of MC-targeted therapeutics to provide a comprehensive perspective on the prevention and treatment of DKD.