The thermoelectric (TE) phenomenon, which involves the direct interconversion of heat and electricity, holds huge promise for green energy generation and refrigeration. The TE option, however, faces a major materials bottleneck-the TE conversion efficiency of known materials is very low, which seriously restricts their application in real-life devices. A substantial amount of effort has been directed during the past three decades to design and develop new materials with enhanced TE conversion efficiency. In this regard, 2D semiconductors have attracted special attention in recent times due to the novel transport mechanisms observed in such materials. Many 2D semiconductors allow independent tuning of electrical and thermal conduction while maintaining reasonably high thermal voltage gradient, which is a prerequisite for enhanced TE efficiency. In this chapter, we discuss the challenges and opportunities of some important 2D semiconductors as potential high-efficiency TE materials.