An effective method for performing the thermal optimization of fully confined pin-fin heat sinks under constraints of pressure drop, mass, and space limitations has been successfully developed. This study shows how automated design optimization techniques can be successfully applied to optimal design of pin-fin heat sinks, which allows the thermal engineer to meet several design objectives and constraints simultaneously. The thermal and hydrodynamic models for pin-fin heat sinks have been developed. A statistical method for sensitivity analysis of the design factors, including the size of heat source and sink footprint, conductivity of sink base, fin material, fin pitch, fin diameter, fin height, thickness of sink base, and upstream mass flowrate, is performed to determine the key factors that are critical to the design. A response surface methodology is then applied to establish regression models for the thermal resistance and pressure drop in terms of the design factors with an experimental design. By employing the gradient-based numerical optimization technique, a series of constrained optimal designs can be efficiently performed. Comparisons between these predicted optimal designs and those evaluated by the theoretical calculations and numerical simulations are made with satisfactory agreements.