Background: Though it is well appreciated that insulin plays an important role in regulating muscle protein metabolism, there is much discrepancy in the literature on the capacity of exogenous insulin administration to increase muscle protein synthesis rates in vivo in humans. Objective: To assess whether exogenous insulin administration increases muscle protein synthesis rates in young and older adults. Design: A systematic review of clinical trials was performed and the presence or absence of an increase in muscle protein synthesis rate was reported for each individual study arm. In a stepwise manner, multiple models where constructed that excluded study arms based on the following conditions: model 1) concurrent hyperaminoamino-acidemia, model 2) insulin-induced hypoaminoacidemia, model 3) supraphysiological insulin concentrations, and model 4) older, more insulin resistant, subjects. Conclusions: From the presented data in the current systematic review, we conclude that 1) exogenous insulin and amino acid administration effectively increase muscle protein synthesis, however this effect is attributed to the hyperaminoacidemia, 2) exogenous insulin administrated systemically induces hypoaminoacidemia which obviates any insulin-stimulatory effect on muscle protein synthesis, 3) exogenous insulin resulting in supraphysiological insulin levels exceeding 50,000 pmol/L may effectively augment muscle protein synthesis, 4) exogenous insulin may have a diminished effect on muscle protein synthesis in older adults due to age related anabolic resistance, and 5) exogenous insulin administrated systemically does not increase muscle protein synthesis in healthy, young adults.