Until now, the clinical investigation of the pineal endocrine activity has been substantially limited to the evaluation of its most known hormone, the indole MLT, whose secretion is characterized by a light/dark circadian rhythm, with high levels during the dark phase of the day and low during the light period [2]. Moreover, MLT secretion has appeared to change during the life and to dramatically decline with the pubertal development [11]. In fact, the decrease in the nocturnal levels of MLT would constitute the first endocrine sign of the sexual development, which precedes the occurrence of LH peaks during the night [11]. Finally, after the onset of puberty, MLT progressively declines with age until the disappearance of its circadian rhythm, with, however, important individual variations [12]. A diminished MLT endogenous secretion with a loss of its light/dark rhythm has been documented in all human system diseases, including advanced tumours [13], autoimmune pathologies [14], brain and cardiac ischemic diseases [15], and neurodegenerative and neuropsychiatric disorders [16]. Then, because of its anti-inflammatory, anti-tumor and antioxidant activities, the progressive decline in MLT secretion could contribute to the pathogenesis of human chronic systemic diseases and to their clinical evolution. Obviously, the evaluation of the other pineal indole hormones, namely the 5-methoxytryptamine [17], and beta-carbolines [18], the most known of them is the pine line, will be necessary to better define the pineal function in the human physiology. As far as ACE-ACE2 system, its functionless may be investigated by simply detecting the blood levels of the products of the enzymatic activity of both ACE and ACE2, respectively consisting of Ang II and Ang 1-7. Therefore, Ang II-to-Ang 1-7 ratio could constitute a synthetic biomarker to define the in vivo functionless of ACE-ACE2 system. As well as shown for MLT, human systemic inflammatory and ischemic diseases have been also found to be characterized by a concomitant decline in the endogenous production of Ang 1-7, due to a diminished ACE2 expression with respect to that of ACE2 [19,20]. In fact, abnormally low blood levels of Ang 1-7 in association with a concomitant increase in those of Ang II have been documented in cardiovascular disorders [21], advanced neoplasms [22], autoimmune diseases [23], neurodegenerative pathologies [24], and metabolic syndrome [25]. Because of its hypotensive activity and its cardioprotective regenerative effects, Ang 1-7 could become one of the main drugs in the treatment of cardiac and vascular dysfunctions [21]. Ang 1-7 has been proven to be effective also in the treatment of pulmonary arterial hypertension. The efficacy of Ang 1-7 in the therapy of metabolic syndrome is due to its inhibitory action on adipocyte-related enhanced production of inflammatory cytokines, which may allow to the insulin resistance and to alterations in lipid metabolism [25]. Moreover, it has been shown that there is an ACE-ACE2 system also at brain level, and that a diminished expression of ACE2 with a consequent Ang 1-7 deficiency may promote both brain neurodegenerative and ischemic disorders [24]. Aging itself is characterized by a diminished Ang 1-7 secretion [5,6,19,20]. This evidence is not surprising by considering that Ang 1-7 exerts hypotensive, cardioprotective, anti-tumor, immunomodulating, neurotrophic effects [5,6], and may prevent the occurrence of insulin resistance [25]. Therefore, the diminished endogenous production of MLT and Ang 1-7 induced by pineal and ACE2 deficiencies could represent the main common pathologic mechanism, which characterizes the overall human inflammatory diseases, irrespectively of their clinical features. This statement is justified by the fact that all human diseases are characterized by an enhanced inflammatory status. Then, because of the fundamental anti-inflammatory role of ACE2-Ang 1-7 axis and the pineal gland either directly or through its connection with cannabinoid system and oxytocin [26], MLT and Ang 1-7 deficiencies would allow a chronic inflammatory status, which represents the common mechanism of human systemic diseases. The importance of the anti-inflammatory action of MLT and Ang 1-7 is furtherly remarked by the fact that most cytokines of the cytokine network are provided by inflammatory activity. Then, the control of the biological inflammatory response is physiologically firstly realized by a neuroendocrine control, mainly mediated by the pineal gland and ACE2-Ang 1-7 axis, rather than through cytokine network itself. Therefore, systemic disease-related inflammatory status could not directly be due to a primary immune cell dysfunction, but at least in part on an altered neuroendocrine regulation of the immunoinflammatory response. The main connection between neuroendocrine system and cytokine network would be played by IL-17, mainly released from Th17 lymphocytes, which has been proven to inhibit ACE2 expression and the consequent Ang 1-7 production [27], and whose secretion is inhibited by both MLT [28] and Ang 1-7 [29]. IL-17 has appeared to induce direct cardiovascular alterations, including ischemic and thrombotic disorders [30]. Then, MLT and Ang 1-7-induced inhibition of IL-17 secretion could represent one of the main mechanisms responsible for the protective biological properties of both MLT and Ang 1-7 themselves. Finally, it has been shown that the progressive increase in the endogenous production of IL-17 would constitute one of the main aging-related changes in the immune functionless [31], with a consequent predisposition to both cancer and autoimmunity because of the promoting role of IL-17 on both cancer progression and autoimmune processes [32].