OBJECTIVES: Rare diseases affect a significant proportion of global population. Several challenges exist for healthcare systems trying to provide integral care for rare diseases patients, as well as for the inclusion of orphan drugs. The purpose of this article is to perform a systematic review of the literature of the alternatives used by health care systems worldwide, in order to identify and synthesize their components and processes. This is an essential step to develop a healthcare model for Colombia.  METHODS: We created a multidisciplinary panel composed by 30 methodological experts, clinicians and different stakeholders from patient associations and institutions involved in rare diseases. This panel validated the PICOT question and the search strategy in the selected electronic databases for the systematic review. Quality of evidence was evaluated with NOTARI tool. We then synthesized available information and organized it in analytical components. Subsequent contributions by experts were then incorporated using a modified Delphi technique. RESULTS: A total of 147 papers were included in the analysis. Ten key components were identified after analyzing international models: policy and legislation, definition and coding, research and education, centers of excellence and networks for healthcare, diagnosis and screening, inclusion of orphan drugs, patient rehabilitation, patient organizations, social support, and administrative aspects. All information was organized in these categories in a descriptive and comprehensive way, which will be discussed in an open forum at the Colombian Academy of Medicine on the International Rare Diseases Day (Monday February 29). CONCLUSIONS: We identified ten key components of models of healthcare for rare diseases. These pillars govern the organizational structure and action plan of each country depending on their political, social and economic context. The next challenge is to identify which concrete actions are feasible in the present Colombian situation.