This text outlines the empirical research, theoretical underpinnings, and clinical application of a novel supportive-expressive psychotherapy for patients with metastatic cancer and their caregivers. Managing Cancer and Living Meaningfully, known by its acronym of CALM, provides a framework for therapists with diverse backgrounds and training to help patients and their caregivers to address the practical and profound challenges of advanced cancer and to live their lives as meaningfully as possible. CALM provides reflective space for them to consider treatment decisions and communication with their health care providers, disruptions in identity, attachment security and the sense of meaning in their life, and to address fears, hopes, and concerns related to the end of life. Particular attention is paid in CALM to the regulation of affect, to the renegotiation of attachment relationships and to helping patients and their caregivers to sustain “double awareness” of the possibilities for living, while also managing their disease and planning for the end of life. Such an approach not only helps to prevent depression and death anxiety, but also helps to reclaim the loss of the imaginative possibilities for living in the context of all-consuming cancer care. The universal dimensions of advanced cancer and the semi-structured nature of CALM permit it to be delivered in the language and cultural idiom of cancer treatment settings in virtually all parts of the world. This text provides the most comprehensive and up-to-date description of the evidence base for CALM, its theoretical foundations and a manualized guide to its clinical application, filled with rich clinical illustrations.