Phosphatidylinositol-4,5-bisphosphate (PIP2) has emerged as a versatile regulator of TRP ion channels. In many cases, the regulation involves interactions of channel proteins with the lipid itself independent of its hydrolysis products. The functions of the regulation mediated by such interactions are diverse. Some TRP channels absolutely require PIP2 for functioning, while others are inhibited. A change of gating is common to all, endowing the lipid a role for modulation of the sensitivity of the channels to their physiological stimuli. The activation of TRP channels may also influence cellular PIP2 levels via the influx of Ca2+ through these channels. Depletion of PIP2 in the plasma membrane occurs upon activation of TRPV1, TRPM8, and possibly TRPM4/5 in heterologous expression systems, whereas resynthesis of PIP2 requires Ca2+ entry through the TRP/TRPL channels in Drosophila photoreceptors. These developments concerning PIP2 regulation of TRP channels reinforce the significance of the PLC signaling cascade in TRP channel function, and provide further perspectives for understanding the physiological roles of these ubiquitous and often enigmatic channels.