The study of factors that influence blood glucose homeostasis is becoming increasingly important as prevalence rates for insulin resistance and type 2 diabetes have increased. Diets with a low glycemic index (lowGI) have been shown to reduce the risk for diseases by limiting the increase of glucose in the blood. LowGI intake in one meal also has been shown to limit the postprandial glycemic response (PPGR) to a subsequent meal; a concept termed the “second meal effect”. Although there have been many theories for the mechanisms responsible for the second meal effect, the exact cause has yet to be elucidated. It is important for both research investigators as well as patients to consider food consumption prior to testing PPGR, as there is evidence that the GI of one meal not only affects the PPGR of that meal, but will also influence the PPGR of the following meal(s). Here we will review recent evidence regarding factors believed to contribute to the second meal effect and the magnitude of their impact.