The cellular and molecular site and mode of action of acrylamide (ACR) leading to neurotoxicity has been investigated for four decades, without resolution. Although fast axonal transport compromise has been the central theme for several hypotheses, the results of many studies appear contradictory. Our analysis of the literature suggests that differing experimental designs and parameters of measurement are responsible for these discrepancies. Further investigation has demonstrated consistent inhibition of the quantity of bi-directional fast transport following single ACR exposures. Repeated compromise in fast anterograde transport occurs with each exposure. Modification of neurofilaments, microtubules, energy-generating metabolic enzymes and motor proteins are evaluated as potential sites of action causing the changes in fast transport. Supportive and contradictory data to the hypothesis that deficient delivery of fast-transported proteins to the axon causes, or contributes to, neurotoxicity are critically summarized. A hypothesis of ACR action is presented as a framework for future investigations.