This paper investigates multiple degree of freedom (MDOF) optimization of steady-state vapor-compression cycle (VCC) operation. Five degrees of freedom (DOFs) of the VCC are optimized using an objective function which minimizes the rate of exergy destruction in the cycle. The use of exergy is motivated by its ability to capture the physics of both the first and second laws of thermodynamics in a single property. A case study is considered in which the optimization is applied to a commercial truck transport refrigeration system (TTRS). The results suggest that by using the optimal set points generated by the exergy-based objective function, an increase of 52.5% in COP can be achieved over nominal operation. In particular, the optimization results highlight the regulation of evaporator and condenser pressure as critical parameters in improving the efficiency of steady-state cycle operation.