Objective: Individuals may experience a wide range of psychological reactions in response to negative life events. Even if events that threaten life have been always played a central role in research, recent studies have outlined that experiences, considered exceptional but part of the human existence (e.g., divorce, unemployment, or chronic illness) may also lead individuals to experience enduring emotional states of suffering. Demoralization has been substantially described as an important condition occurring in response to stressful events, while a recent interest is growing on embitterment as a common reaction. Method: By analyzing the most relevant studies (MEDLINE, EMBASE, PsycLit, and Cochrane Library), this article discusses the main features of embitterment and demoralization, summarizing the similarities as well as the differences detectable between the 2 constructs. Results: Some authors have described these phenomena as spectrum or gradients that start with normal human responses until getting to pathological conditions, characterized by prolonged intense psychological distress in relation to stressful events. Both have shown distinct psychopathological features than other stress-related mental disorders and have been recognized as predictors of negative outcomes, such as impairment in work and social functioning, reduction of quality of life, risk for mental and physical disorders, and suicidality. Conclusions: Demoralization and embitterment are multidimensional phenomena, connected to each other by bridge dimensions and in the meanwhile characterized by distinct features. Accurately exploring these clinical conditions is an ongoing challenge to clinicians and researchers, who are called for improving their recognition and proper therapeutic interventions that can ameliorate patients quality of life.