The ligand deorphanization of TRP channels has a tremendous potential for biomedical and nutritional research, and this review highlights the role that natural products have played in the identification of ligands for these targets and their establishment as viable candidates for drug discovery. Specific ligands have so far been discovered only for some thermoTRPs, like TRPV1, TRPV3, TRPV4, TRPM8 and TRPA1, and the lack of selective pharmacology has been a major drawback for unraveling the biological role of TRPs. While genetic approaches (transgenic animal models) have partially compensate for the lack of ligands, the universal expression of TRPs in living systems and the success achieved with TRPV1 suggest that a systematic investigation of the natural products pool might alleviate this shortage, fostering adoption by small molecules within this class of still largely orphan biological targets.