Thermoelectric coolers (TECs) are solid-state cooling devices that operate on the Seebeck effect. They can be used in electronic cooling applications as well as other refrigeration systems. Among the various factors that affect TEC performance within a system, it has been shown that the thermal conductance is an important parameter, which can also be easily altered during the design of a TEC to deliver optimal TEC performance for a given application. However, these studies have considered only a fixed heat load and heat sink temperature, whereas in many realistic applications these quantities can vary. A procedure has been developed for optimizing the thermal conductance of a TEC based on a typical operating cycle of time-varying heat load and sink temperature, while permitting constraints that ensure that one or more worst-case operating conditions can also be met. This procedure is valid for any arbitrary heat load and sink temperature functions; however, for illustrative purposes, a simple heat load function at fixed sink temperature (and a sink temperature function at fixed heat load) is used. The results show that the optimal conductance can strongly depend on the operating cycle, and the corresponding reduction in electrical input work (and corresponding increase in net coefficient of performance (COP)) can be significant.