Recent studies have introduced the importance of transient receptor potential vanilloid subtype 4 (TRPV4) channels in the regulation of vascular tone. TRPV4 channels are expressed in both endothelium and vascular smooth muscle cells and can be activated by numerous stimuli including mechanical (eg, shear stress, cell swelling, and heat) and chemical (eg, epoxyeicosatrienoic acids, endocannabinoids, and 4α-phorbol esters). In the brain, TRPV4 channels are primarily localized to astrocytic endfeet processes, which wrap around blood vessels. Thus, TRPV4 channels are strategically localized to sense hemodynamic changes and contribute to the regulation of vascular tone. TRPV4 channel activation leads to smooth muscle cell hyperpolarization and vasodilation. Here, we review recent findings on the cellular mechanisms underlying TRPV4-mediated vasodilation; TRPV4 channel interaction with other proteins including transient receptor potential channel 1, small conductance (K(Ca)2.3), and large conductance (K(Ca)1.1) calcium-activated potassium-selective channels; and the importance of caveolin-rich domains for these interactions to take place.