New-onset diabetes mellitus after transplantation (NODAT) is a serious complication in organ transplantation; not only does it enhance the risk of graft dysfunction, it also increases cardiovascular morbidity and mortality. The mammalian target of rapamycin (mTOR) is regulated independently by insulin, amino acids, and energy sufficiency. It integrates signal from growth factors, hormones, nutrients, and cellular energy levels to regulate protein translation and cell growth, proliferation, and survival. In addition, mTOR generates an inhibitory feedback loop on insulin receptor substrate (IRS) proteins. Therefore, it was suggested that mTOR might link nutrient excess with both obesity and insulin resistance. In this review, we summarize the role of mTOR and its inhibitor sirolimus (SRL) on chronic hyperglycemia and insulin resistance in beta cells, adipose tissue, liver, and muscle. We further hypothesize, based on data from the literature and generated in our laboratory, that SRL could counteract the development of NODAT in stable glucose homeostasis due to its positive effects on insulin-stimulated glucose uptake, whereas in conditions that require an adaptive beta cell proliferation (such as pregnancy and weight increase), the administration of SRL might have effects that would promote the development of NODAT. Therefore, it seems crucial for patient outcome to consider these potentially contrasting effects of SRL.