Health, as defined by the World Health Organization, encompasses physical, mental, social, and spiritual well-being. However, in the context of serious illnesses such as cancer, the biological aspects are prioritized in healthcare which leaves a gap in addressing patients’ holistic well-being. This chapter reviews the psychosocial approach to cancer care, emphasizing a comprehensive assessment. Screening is usually the first clinical component for health professionals to address distress and potential problems that a patient may experience during his/her illness trajectory. A “comprehensive” assessment that covers physical, psychiatric, socioeconomic, psychological, and spiritual domains helps evaluate the bio-psycho-social concomitants of cancer more specifically. Clinicians are encouraged to address each of the five areas in a hierarchical order since higher-level problems (e.g., physical domain) can have an impact on lower-level problems (e.g., psychological domain). Problems at a lower level may decrease if a concern at a higher level is relieved. The physical domain of comprehensive assessment involves evaluating the symptoms and illness understanding of a patient. The use of validated instruments such as the Edmonton Symptom Assessment Scale is recommended. As a part of psychiatric assessment, psychiatric disorders due to physical conditions, drug-induced psychiatric disorders, and physical disorders that present with (“mimics”) psychological and psychiatric symptoms should be included in key differential diagnoses. Socioeconomic assessment addresses practical and social problems. Psychological assessment involves understanding coping mechanisms and emotional reactions and distinguishing between normal stress responses and clinical diagnoses. Spiritual considerations, which are vital in cancer care, encompass existential challenges. A comprehensive assessment guides tailored interventions, including basic support, counseling, a multidisciplinary team approach, and more specific psycho-oncology treatments, employing evidence-based psychotherapies and psychopharmacological interventions. It underscores the imperative for healthcare professionals to adopt a holistic psychosocial approach in cancer care, acknowledging the intricate interplay of physical, psychological, social, and spiritual elements in enhancing patient well-being.