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The maintenance of stable vascular tone is functionally important for buffering flow and redistributing blood oxygen and glucose to match the metabolic demands of organs and tissues. As the tone of other hollow organs, build by smooth muscle cells, vascular tone is governed by the reversible phosphorylation of the 20-kDa regulatory light chains of myosin (MLC₂₀) controlled by two opposing enzymes: the calcium/calmodulin (Ca²⁺-CaM)-activated myosin light chain kinase (MLCK), which phosphorylates MLC₂₀, and myosin light chain phosphatase (MLCP), which dephosphorylates it. In this review, we summarize the key aspects of tone regulation across different brain regions and peripheral vascular beds, with particular emphasis on the central role of the enzyme myosin light chain phosphatase (MLCP) in both physiological and pathological contexts. We propose that MLCP functions as a central molecular integrator of Ca²⁺-dependent, RhoA/ROCK-mediated, cyclic nucleotide-dependent, redox- and hypoxia-sensitive, and splice variant-controlled signalling pathways that collectively determine vascular tone. Finally, we discuss clinically relevant perspectives for research aimed at improving the management of diseases associated with impaired MLCP function.