Gestational diabetes mellitus (GDM) is the most common metabolic disease of pregnancy, associated with several perinatal complications. Adequate glycemic control has been proved to decrease risk of GDM-related complications. Several studies have shown the beneficial effect of exercise and medical nutrition treatment on glycemic and weight control in GDM-affected women. Moreover, pharmacological agents, such as insulin and specific oral anti-diabetic agents can be prescribed safely during pregnancy, decreasing maternal blood glucose and, thus, perinatal adverse outcomes. Multi-disciplinary treatment approaches that include both lifestyle modifications (medical nutritional therapy and daily physical exercise) and pharmacological treatment, in cases of failure of the former, constitute the most effective approach. Insulin is the gold standard pharmacological agent for GDM treatment. Metformin and glyburide are two oral anti-diabetic agents that could serve as alternative, although not equal in terms of effectiveness and safety, treatment for GDM. As studies on short-term safety of metformin are reassuring, in some countries it is considered as first-line treatment for GDM management. More studies are needed to investigate the long-term effects on offspring. As safety issues have been raised on the use of glyburide during pregnancy, it must be used only when benefits surpass possible risks.