The Na,K-ATPase is an enzyme essential for ion homeostasis in all cells. Over the last decades, it has been well-established that in addition to the transport of Na ⁺ /K ⁺ over the cell membrane, the Na,K-ATPase acts as a receptor transducing humoral signals intracellularly. It has been suggested that ouabain-like compounds serve as endogenous modulators of this Na,K-ATPase signal transduction. The molecular mechanisms underlying Na,K-ATPase signaling are complicated and suggest the confluence of divergent biological pathways. This review discusses recent updates on the Na,K-ATPase signaling pathways characterized or suggested in vascular smooth muscle cells. The conventional view on this signaling is based on a microdomain structure where the Na,K-ATPase controls the Na,Ca-exchanger activity via modulation of intracellular Na ⁺ in the spatially restricted submembrane space. This, in turn, affects intracellular Ca ^{2 +} and Ca ^{2 +} load in the sarcoplasmic reticulum leading to modulation of contractility as well as gene expression. An ion-transport-independent signal transduction from the Na,K-ATPase is based on molecular interactions. This was primarily characterized in other cell types but recently also demonstrated in vascular smooth muscles. The downstream signaling from the Na,K-ATPase includes Src and phosphatidylinositol-4,5-bisphosphate 3 kinase signaling pathways and generation of reactive oxygen species. Moreover, in vascular smooth muscle cells the interaction between the Na,K-ATPase and proteins responsible for Ca ^{2 +} homeostasis, e.g., phospholipase C and inositol triphosphate receptors, contributes to an integration of the signaling pathways. Recent update on the Na,K-ATPase dependent intracellular signaling and the significance for physiological functions and pathophysiological changes are discussed in this review.