CONTEXT: Existential and spiritual concerns in relation to palliative end-of-life care have received increasing attention over the past decade. OBJECTIVES: To review the literature specifically related to existential suffering in palliative care in terms of the significance of existential suffering in end-of-life care, definitions, conceptual frameworks, and interventions. METHODS: A systematic approach was undertaken with the aim of identifying emerging themes in the literature. Databases using CINAHL (1980-2009), MEDLINE (1970-2009), and PsychINFO (1980-2009) and the search engine of Google Scholar were searched under the key words existential suffering, existential distress, existential pain, palliative and end of life care. RESULTS: The search yielded a total of 156 articles; 32% were peer-reviewed empirical research articles, 28% were peer-reviewed theoretical articles, and 14% were reviews or opinion-based articles. After manually searching bibliographies and related reference lists, 64 articles were considered relevant and are discussed in this review. Overall analysis identifies knowledge of the following: 1) emerging themes related to existential suffering, 2) critical review of those identified themes, 3) current gaps in the research literature, and 4) recommendations for future research. Findings from this comprehensive review reveal that existential suffering and deep personal anguish at the end of life are some of the most debilitating conditions that occur in patients who are dying, and yet the way such suffering is treated in the last days is not well understood. CONCLUSION: Given the broad range of definitions attributed to existential suffering, palliative care clinicians may need to be mindful of their own choices and consider treatment options from a critical perspective.