Contractile abnormalities of vascular smooth muscle (VSM) are considered to underlie many diseases/disorders, including hypertension and diabetes-associated vascular abnormalities. Tone management is a key contribution of the VSM, which when functioning normally, contributes to general health and wellness but when dysfunctional is associated with morbidity and mortality. Of central importance to the development of pathological alterations in VSM is alterations in distinct signal transduction proteins that regulate fine control of tone and maintain normal cardiovascular function. The zipper-interacting protein kinase (ZIPK) is a widely expressed Ser/Thr protein kinase that has emerged as a critical regulator of a number of biological processes, including cell division and cytokinesis, cell proliferation and apoptosis, cell motility and smooth muscle contraction. A novel pyrazolo[3,4-d]pyrimidinone (HS38) inhibitor of ZIPK that lacks off-target effects against other contractile kinases was recently developed. In cellular studies, HS38 decreased myosin (LC20) phosphorylation. In ex vivo studies, HS38 decreased contractile force of arterial smooth muscle strips by decreasing LC20 and myosin phosphatase (MYPT1) phosphorylation. In addition, recent studies with pressure myography suggest ZIPK regulates myogenic responses to changing intraluminal pressure. Furthermore, a hypercontractile phenotype in cerebral vessels isolated from the spontaneous hypertensive rat (SHR) model was linked to ZIPK-dependent increases in VSM force. Application of HS38 resulted in a ~60% reduction in the magnitude of myogenic contractions over the 60-120 mmHg pressure range. These data suggest that modulation of ZIPK activity may be a prime determinant for development of hypertension, and the recent availability of a validated ZIPK inhibitor provides an opportunity to target aspects of ZIPK signaling in VSM biology that were previously not attainable.