Compliance with treatment is crucial to the optimal management of any chronic disease. Non-compliance with antihyperglycemic treatment is clearly a significant issue for patients with type 2 diabetes mellitus as it decreases the efficacy of the treatment and increases the risk of developing microvascular and macrovascular complications, therefore increasing the human and economic costs of this disease. The effect of low compliance on metabolic control has been shown to represent an increase of up to 1.4% in glycosylated hemoglobin. Achieving optimal compliance is therefore a therapeutic objective of prime importance. Many factors have been cited as contributing to poor compliance. Some of these, such as age, severe complications and disabilities, and social, educational, and financial difficulties, affect compliance with treatment in quite a significant manner, but are not modifiable by the healthcare provider. Other factors, such as the number of tablets per dose and polymedication, are modifiable but do not appear to be of major importance, whereas the frequency of administration is both an important and a modifiable factor affecting compliance with treatment. One strategy for optimization of compliance involves treatment of type 2 diabetes using oral antihyperglycemic agents with once-daily formulations. Recent data indicate that reducing the daily administration frequency of oral antihyperglycemic agents improves compliance with treatment and consequently metabolic control. Therefore, optimization of treatment through a reduction in the frequency of antihyperglycemic administration could be a valuable weapon in the battle to improve health outcomes and reduce the burden of type 2 diabetes.