Vasopressin (AVP) and copeptin are released in equimolar amounts from the same precursor. Due to its molecular stability and countless advantages as compared with AVP, copeptin perfectly mirrors AVP presence and has progressively emerged as a reliable marker of vasopressinergic activation in response to osmotic and hemodynamic stimuli in clinical practice. Moreover, evidence highlighting the prognostic potential of copeptin in several acute diseases, where the activation of the AVP system is primarily linked to stress, as well as in psychologically stressful conditions, has progressively emerged. Furthermore, organic stressors induce a rise in copeptin levels which, although non-specific, is unrelated to plasma osmolality but proportional to their magnitude: suggesting disease severity, copeptin proved to be a reliable prognostic biomarker in acute conditions, such as sepsis, early post-surgical period, cardiovascular, cerebrovascular or pulmonary diseases, and even in critical settings. Evidence on this topic will be briefly discussed in this article.