Tuberculosis (TB) is known to be fueled by HIV as well as social and economic factors. With progression of the diabetes mellitus (DM) pandemic in countries where TB is also endemic, focus is increasing on the potential links between DM and TB. Despite the magnitude of the DM-TB association woldwide, it is striking how little we know about the underlying biology that promotes this association which is a major concern to public health. In this review we summarize current findings regarding the alterations in the innate and adaptive immune responses of DM patients to Mycobacterium tuberculosis (Mtb). Current findings suggest underperforming innate immunity followed by a hyper-reactive cellular response to Mtb, but the contribution of these altered responses to TB susceptibility or to the more adverse clinical outcomes of TB patients with DM remains unclear. Elucidating the basic mechanisms underlying the higher susceptibility of DM patients to TB should lead to a strategy for stratification of the millions of DM patients worldwide into those with the highest TB risk for targeted TB prevention.