Background: Multimorbidity (the co-occurrence of two or more chronic diseases) can be seen as a prototypical situation in which psychosocial adjustment is required. Even though most patients adapt successfully, a significant number of individuals show adaptation problems and develop additional mental health problems. Objective: For this reason, this article focuses on the importance of psychosocial adaptation as a core process in the context of quality of life. Results: Important findings pointing at the association between multimorbidity and mental health are summarized, and the stress-response perspective on psychosocial adjustment is introduced. Furthermore, cognitive-affective processing of the disease (in the context of illness perceptions) and interpersonal emotion regulation are presented as relevant examples for processes involved in psychological adaptation to multimorbidity. As an intervention possibility, expressive writing is given as a feasible example. Conclusion: Viewing adjustment problems to multimorbidity from a stress-response perspective offers a framework for a deeper understanding of core processes regarding multimorbidity and quality of life that is not only important for research but also for clinical practice. This article ends with a general summary and an outlook on clinical implications of the introduced stress-response concept of adjustment to multimorbidity.