Calcium-permeable transient receptor potential cation channel subfamily V member 4 (TRPV4) channels, first described in 2000, are activated by osmotic, mechanical, thermal, actinic, and chemical cues; play multiple roles in multiple physiologic processes, organ systems, and diseases; and are expressed in diverse cell lineages, with channel function-expression regulated by metabolic and endocrine state, inflammation, mechanical microenvironment, and other forms of cellular stress. Here, I will focus on TRPV4's role in endothelia, citing three examples that can guide translational efforts and development of TPRV4-focused therapeutics. (i) Peroxynitrite-dependent impairment of endothelial TRPV4 drives obesity-related hypertension. (ii) Blood-brain barrier in MS: TRPV4 drives endothelial inflammation and pro-inflammatory interaction between endothelia and microglia in active lesions. (iii) Gain-of-function spinal cord endothelial TRPV4 causes spinal muscular atrophy via developmental barrier impairment, leakage, and subsequent motoneuron injury. Thus, different pathophysiologic mechanisms need to be met with different strategies when selectively targeting endothelial TRPV4, namely restoration of impaired function (i), versus inhibition of excessive function (ii)-(iii).