Drug-like compounds that exert biological activity towards TRP channels are either being used as cell biological tools or further developed into pharmacological lead structures aiming at therapeutic use in diseased states. Although drug-likeliness is not easy to predict, common rules include a relatively low molecular weight, physicochemical constraints, and the absence of known reactive or otherwise toxic groups. Small molecules that exert a biological activity to block, activate, or modulate TRP channels are intensely sought. Such tool compounds may be useful to assign native currents to a certain TRP channel and to validate the channel as a candidate target for future pharmacological intervention. Depending on the TRP channel isotype, these activities have reached different levels, with only few TRP channels modulators already being clinically tested in humans, whereas other compounds only underwent a preliminary validation. For some TRP channels, reliable low molecular weight inhibitors are not yet available. Hence, further efforts need to be undertaken in order to explore the physiological impact and possible therapeutic potential of TRP channel targeting with drug-like compounds.