Type 2 diabetes (T2D) is a progressive disorder with a consistent and steady increase in glycosylated hemoglobin (HbA1c) over time associated with enhanced risk of micro- and macrovascular complications and a substantial reduction in life expectancy. There are three major pathophysiologic abnormalities associated with T2D: impaired insulin secretion, excessive hepatic glucose output, and insulin resistance in skeletal muscle, liver, and adipose tissue. These defects have been treated in clinical praxis by use of oral insulin secretagogues (sulfonylureas/glinides) or insulin, biguanides, and thiazolidinediones (TZDs) respectively. Pioglitazone HCL is an insulin sensitizer in the TZD family and glimepiride is an insulin secretagogue in the SU family. This article reviews mechanisms of action and clinical data behind the use of these two commonly used oral hypoglycemic agents with documented efficacy and good safety profile of once-daily administration, alone or in combination with insulin or metformin, in the management of T2D in terms of glycemic and non-glycemic effects, tolerability and side effects, and impact on vascular health.