To explore patients’ existential challenges when living with chronic pain or multiple sclerosis, 23 semistructured patient interviews were conducted together with an interpretative, phenomenological analysis inspired by Søren Kierkegaard. Patients experienced their illness as a “stroke of fate” resulting in despair and a profound struggle to find out, who they were, and how they could relate to themselves in their new life-situation. Becoming oneself was experienced as a long-term existential process realized by synthesizing the existential poles of necessities and possibilities through “the other,” such as relationships, nature, spirituality, or God. The different ways to respond to the existential challenges were identified as subjective choices of aesthetic, ethic, and religious life-spheres. The Kierkegaardian relational self and the life-spheres as diverse possibilities are valuable for understanding patients’ existential challenges and the complicated process of finding a new way to relate to oneself when life is fundamentally transformed by illness. To resolve the existential struggles, it seems essential to take a subjective stand in life and have a relationship to something bigger than oneself. The findings can inform clinical practice and inspire health care professionals to identify patients who would welcome a dialogue about illness-related existential struggles for the benefit of their health.