Abstract Purpose The growing group of patients who suffer from chronic cancer-related fatigue (CCRF) after cancer have helpful and less helpful ways of responding to this long-lasting and disruptive problem. This qualitative study aimed to gain insight in essential elements of how patients respond to CCRF, with a focus on helpful responses to facilitate adaptation. Methods We conducted semi-structured interviews with a purposive sample of 25 participants who experienced severe CCRF for at least 3 months. Participants were recruited via media, patient associations, meetings, and health professionals until data saturation was attained. We used a topic guide with open-ended questions about lived experiences. Interpretative phenomenological analysis (IPA) was used for analysis of the transcripts. Results We identified five interrelated themes of how patients respond to CCRF: (1) discovering physical and emotional boundaries; (2) communicating support needs; (3) reorganizing and planning activities and rest; (4) letting go of one’s habitual identity; and (5) recognizing and accepting CCRF. Conclusion This study highlights the development of new habits and positive beliefs in the face of CCRF and the importance of (social) support in this process. This experiential knowledge on helpful responses can be used to inform patients and their significant others and improve self-efficacy. Health professionals could use these insights to improve recognition of CCRF and personalize treatment.