As demonstrated by suboptimal levels of therapeutic goal achievement, there exists significant room for improvement in type 2 diabetes management. Despite widespread disease awareness and high rates of risk-factor testing in managed care, effective metabolic control in patients with type 2 diabetes is lacking and points toward a phenomenon known as clinical inertia. Clinical inertia, defined as a failure to initiate or advance therapy in a patient who is not at the evidence-based goal, is a key contributing factor in the suboptimal rates of therapeutic target achievement for type 2 diabetes. The causes of clinical inertia are multifactorial and interactive, arising among patients, providers, and health systems and from specific characteristics of available treatments. Therapeutic nonadherence is perhaps the most significant factor contributing to clinical inertia, with recent analyses demonstrating that providers are more likely to prescribe a dose escalation in patients who are adherent to therapy compared with those who are not. While the concept may be counterintuitive, antihyperglycemic agents also have the potential to cause or contribute to the phenomenon of clinical inertia. This often occurs via factors inherent to the drugs themselves, such as treatment-related adverse effects (eg, hypoglycemia, weight gain, edema, gastrointestinal symptoms), perception of long-term safety profiles, and the complexity of the treatment regimen. Often not considered, but equally important, is the durability of an antihyperglycemic agent to maintain glycosylated hemoglobin (A1C) level goals. Because no monotherapy exists to arrest the pancreatic beta-cell failure of type 2 diabetes, early combination therapy with thiazolidinediones and glucagon-like protein-1 agonists that is associated with sustained A1C level reduction is the only hope to change the progressive nature of type 2 diabetes mellitus.