Nociception is of vital importance for the organism, while its inhibition by endogenous opioid systems is usually a sign of surrender. Therefore, it must be assumed that endogenous analgesic systems are balanced, and in fact, under normal conditions, overwhelmed, by teleologically far more important anti-analgesic systems. The two main anti-analgesic systems--i.e., the melanotropinergic and the cholecystokininergic--are here reviewed for their role, not only in nociception, but in a wide variety of vital functions (endocrine, gastrointestinal, ingestive, reproductive, cardiovascular, immune, etc.). Available data strongly suggest that these systems (particularly the melanotropinergic one) play a key role in the overall homeostasis of the body. Moreover, modulation of endogenous anti-analgesic systems may disclose a new, unforeseen approach to the treatment of pain.