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Thermoelectric coolers are attracting significant attention for replacing age-old cooling and refrigeration devices. Localized cooling by wearable thermoelectric coolers will decrease the usage of traditional systems, thereby reducing global warming and providing savings on energy costs. Since human skin as well as ambient air is a poor conductor of heat, wearable thermoelectric coolers operate under huge thermally resistive environment. The external thermal resistances greatly influence thermoelectric material behavior, device design, and device performance, which presents a fundamental challenge in achieving high efficiency for on-body applications. Here, we examine the combined effect of heat source/sink thermal resistances and thermoelectric material properties on thermoelectric cooler performance. Efficient thermoelectric coolers demonstrated here can cool the human skin up to 8.2 degrees C below the ambient temperature (170% higher cooling than commercial modules). Cost-benefit analysis shows that cooling over material volume for our optimized thermoelectric cooler is 500% higher than that of the commercial modules.