Aspartame is the methyl-ester of the aspartate-phenylalanine dipeptide. Over time it became a very popular artificial sweetener. However, since its approval by the main food safety agencies, several concerns have been raised related to neuropsychiatric effects and neurotoxicity, due to its ability to activate glutamate receptors, as well as carcinogenic risks by increased production of reactive oxygen species. Within this review we critically evaluated reports concerning the safety of aspartame. Some studies evidenced subtle mood and behavioral changes upon daily high-dose intake below the admitted limit. Epidemiology studies also evidenced associations between daily aspartame intake and higher predisposition for malignant diseases like non-Hodgkin lymphomas and multiple myelomas, particularly in males, but association by chance still could not be excluded. While the debate over the carcinogenic risk of aspartame is ongoing, it is clear that its use may pose some dangers in peculiar cases, such as patients with seizures or other neurological diseases; it should be totally forbidden for patients with phenylketonuria, and reduced doses or complete avoidance are advisable during pregnancy. It would be also highly desirable for every product containing aspartame to clearly indicate on the label the exact amount of the substance and some risk warnings.