Epidemiologic and experimental studies suggest that environmental exposures to air pollutants can increase prevalence of metabolic and cardiorespiratory diseases. Among the risk factors, many studies have shown that air pollution, especially by fine particulate matter (PM2.5), can lead to the development of type 2 diabetes mellitus (T2DM) or make diabetics more susceptible to other health complications. This chapter aimed to discuss the pathophysiologic mechanisms evolved in susceptibility to cardiorespiratory PM2.5 effects in T2DM subjects, as well as the enhancing effect of PM2.5 exposure on development of T2DM. We discussed the pathophysiologic mechanisms of PM2.5 exposure and T2DM based on pro−/anti-inflammatory balance, metabolic regulation, redox status, and heat shock response, reinforcing the complex nature of T2DM etiology and highlighting the PM2.5 air pollution as a critical health problem.