Syncope and orthostatic intolerance (OI) are common clinical syndromes often requiring medical attention. The former is defined as transient loss of consciousness and postural tone due to self-limited cerebral hypoperfusion, while the latter consists of inappropriate cardiovascular responses to upright posture such as occur with orthostatic hypotension (OH) or postural orthostatic tachycardia syndrome. The most frequent causes of syncope and OI are conditions that temporarily disrupt essential moment-to-moment interaction between the autonomic nervous system and cardiovascular system. In this regard, many neuropeptides (NPs) or peptide hormones (PH) exert cardioactive effects that might contribute to the pathophysiology of certain forms of syncope or OI. To date, the principal peptides that have been studied in this context are: atrial and B-type-neuropeptides, adrenomedullin, endothelin-1 (ET-1), galanin, and vasopressin. While definitive conclusions cannot yet be drawn, the intrinsic vasoconstrictor ET-1 appears to be elevated in OH, presumably to compensate for vasodilation and hypotension of other etiologies. As such elevated ET-1 may become a marker for OH. Further, elevated NT-proBNP may play a role in causing vasodilation and hypotension in some forms of OH of previously unknown cause, and may be a marker in other patients of a cardiovascular cause of syncope and OI. In the end, the study of the role of NPs and PHs in syncope and OI syndromes is at an early stage, and considerable further future effort is needed.