Reduced smooth muscle (SM)‐specific α2 Na+ pump expression elevates basal blood pressure (BP) and increases BP sensitivity to angiotensin II (Ang II) and dietary NaCl, whilst SM‐α2 overexpression lowers basal BP and decreases Ang II/salt sensitivity. Prolonged ouabain infusion induces hypertension in rodents, and ouabain‐resistant mutation of the α2 ouabain binding site (α2R/R mice) confers resistance to several forms of hypertension. Pressure overload‐induced heart hypertrophy and failure are attenuated in cardio‐specific α2 knockout, cardio‐specific α2 overexpression and α2R/R mice. We propose a unifying hypothesis that reconciles these apparently disparate findings: brain mechanisms, activated by Ang II and high NaCl, regulate sympathetic drive and a novel neurohumoral pathway mediated by both brain and circulating endogenous ouabain (EO). Circulating EO modulates ouabain‐sensitive α2 Na+ pump activity and Ca2+ transporter expression and, via Na+/Ca2+ exchange, Ca2+ homeostasis. This regulates sensitivity to sympathetic activity, Ca2+ signalling and arterial and cardiac contraction. The centrally controlled, parallel sympathetic nerve and slow neurohumoral pathways that regulate both arterial and cardiac function and participate in the pathogenesis of hypertension and heart failure (HF). Angiotensin II (Ang II) and high dietary salt are convergent signals that act via hypothalamic Ang type 1 receptors (AT1R) to activate CNS sympathetic pathways. The increased sympathetic nerve activity (SNA) promotes vasoconstriction and increases cardiac rate and contractile force. Prolonged stimulation of hypothalamic AT1Rs also activates a novel neurohumoral pathway (box at upper right) that includes aldosterone (Aldo), mineralocorticoid receptors (MR), epithelial Na+ channels (ENaC), endogenous ouabain (EO) and α2 Na+ pumps. This hypothalamic pathway feeds back (dashed green line, ‘+’) to modulate Ang II‐activated SNA and also promotes adrenal secretion of EO, triggered by, e.g., ACTH, adrenal SNA and/or Ang II. The elevated plasma EO acutely inhibits α2 Na+ pumps (NKAs) in both the heart and arteries, and the rise in intracellular Na+ rapidly induces Na+/Ca2+ exchanger (NCX)‐mediated Ca2+ gain, and cardiotonic and vasotonic effects. Prolonged plasma EO elevation also activates an α2 Na+ pump‐associated protein kinase cascade (e.g. C‐Src‐mediated) that increases cardiomyocyte (CMC) and arterial smooth muscle cell (ASMC) NCX expression, and arterial sarcoplasmic reticulum (SR) Ca2+ pump (SERCA2) expression. In arteries with tone, NCX normally favours Ca2+ entry and helps to sustain cytosolic Ca2+ (Ca2+CYT) above contraction threshold. The EO‐induced NCX and SERCA2 up‐regulation enhance Ca2+ signalling and help the very modestly increased SNA to increase vascular tone and resistance, and elevate blood pressure. In the heart, NCX promotes Ca2+ extrusion during diastole, but prolonged α2 pump inhibition by EO reduces the Na+ gradient driving force so that Na+CYT and diastolic Ca2+CYT are both elevated; consequently, cardiac relaxation is slow and/or incomplete. Also, cardiac SERCA2 expression is usually reduced in HF (perhaps due to the high EO), as are SR Ca2+ stores and Ca2+ transients, and systolic function is impaired. The diastolic dysfunction and attenuated cardiac contraction and stroke volume help explain HF. This review describes research on mice with genetically engineered α2 Na+ pumps and related studies that elucidate these cellular mechanisms.