The experimental model of chronic inhibition of nitric oxide (NO) production has proven to be a useful tool to study cardiovascular and renal lesions produced by this type of hypertension, which are similar to those found in human hypertension. It also offers a unique opportunity to study the interaction of NO with the humoral systems, known to have a role in the normal physiology of vascular tone and renal function. This review provides a thorough and updated analysis of the interactions of NO with the endocrine system. There is special focus on the main vasoactive factors, including the renin-angiotensin-aldosterone system, catecholamines, vasopressin, and endothelin among others. Recent discoveries of crosstalk between the endocrine system and NO are also reported. Study of these humoral interactions indicates that NO is a molecule with ubiquitous function and that its inhibition alters virtually to all other known regulatory systems. Thus, hypothyroidism attenuates the pressor effect of NO inhibitor N-nitro-L-arginine methyl ester, whereas hyperthyroidism aggravates the effects of NO synthesis inhibition; the sex hormone environment determines the blood pressure response to NO blockade; NO may play a homeostatic role against the prohypertensive effects of mineralocorticoids, thyroid hormones and insulin; and finally, NO deficiency affects not only blood pressure but also glucose and lipid homeostasis, mimicking the human metabolic syndrome X, suggesting that NO deficiency may be a link between metabolic and cardiovascular disease.