Despite the considerable burden of disease associated with type 2 diabetes mellitus (T2DM), most patients are not at, or are unable to achieve, recommended glycemic targets. This is partly because of the relentless progressive nature of the disease, but it may also be attributable to the current diabetes treatment paradigm. The recommended stepwise approach may lead to frequent early treatment failure with prolonged periods of elevated glucose as a consequence of clinical inertia and delays in achieving optimal glycemic control. Thus, it is most appropriate to consider the current treatment paradigm for T2DM in the context of a more aggressive initial therapy with early combination therapy. Current guidelines advise that initial combination therapy should be used for patients presenting with elevated glycated hemoglobin (HbA1c). However, several studies and recent meta-analyses suggest a potential benefit from initial combination therapy on glycemic outcomes in diabetes compared with metformin monotherapy across a wide range of baseline HbA1c levels. Indeed, combination therapy can increase the number of patients achieving glycemic goals, and the newer glucose-lowering agents may reduce the risk of hypoglycemia and body weight gain. Moreover, our improving understanding of the complex pathophysiology of T2DM and the availability of treatments tackling specific mechanisms contributing to hyperglycemia should lead to more pathophysiologically sound combination therapy. We discuss the rationale behind and evidence for early combination therapy as well as what is needed in the future to better understand its potential.