Objective Suffering frequently occurs in the context of chronic and progressive medical illnesses and emerges with great intensity at end-of-life. A review of the literature on suffering and distress-related factors was conducted to illustrate the integrative nature of suffering in this context. We hope it will result in a comprehensive approach, centered in the patient-family unit, which will alleviate or eliminate unnecessary suffering and provide well-being, when possible. Methods An extensive search of the literature on suffering and distress in end-of-life patients was conducted. While the present review is not a systematic one, an in-depth search using the terms 'Suffering', 'Distress', End-of-Life', 'Palliative Care', and 'Terminal illness' was conducted using search engines such as PubMed, PsycINFO, MEDLINE, EBSCO-Host, OVID, and SciELO. Results Taking into account the comprehensive and integrative nature of suffering, factors related to the physical, psychological, spiritual, and social human dimensions are described. As well, some treatment considerations in the palliative care context are briefly discussed. Conclusions Suffering is individual, unique, and inherent to each person. Assessment processes require keeping in mind the complexity, multi-dimensionality, and subjectivity of symptoms and experiences. Optimal palliative care is based on continuous and multidimensional evaluation and treatment of symptoms and syndromes. It should take place in a clinical context where the psychological, spiritual, and socio-cultural needs of the patient-family unit are taken care of simultaneously. A deep knowledge of the nature of suffering and its associated factors is central to alleviate unnecessary suffering.