Background: The objective of this literature review was to identify barriers to access and use of high cost medicines (HCMs). Method: A literature review was performed in common electronic databases (Medline, PubMed, Springer Link, Embase, Science Direct, and Google Scholar). We identified original studies published between 1999 and 2011 relating to access to and use of HCMs. Three hundred and seventy four relevant articles were found. Forty-three original articles matched inclusion criteria. Results: We categorized access barriers into three levels: health system, regional/hospital, and patient levels. Barriers to access included the affordability of the healthcare system, the decision-making process for funding HCMs and eligibility criteria for access, geographic variation in funding and access, communication between physicians and patients, and patient out of pocket costs. Conclusion: Barriers to access HCMs are inter-related. These barriers are also relevant for other medicines but are escalated in the case of HCMs. Overall, healthcare systems are facing barriers related to high out-of-pocket cost for patients and/or barriers regarding the decision-making process and the effects of reimbursement decisions (i.e., restricted, delayed or denied access, particularly the latter for socialized systems with a universal coverage scheme). Inadequate access to HCMs may lead to subsequent use of unnecessary medical treatments. Barriers to access HCMs can also lead to treatment disparities between patients who can overcome these barriers and those who cannot. Improvements in the decision-making process can increase acceptance of the need to prioritize access to HCMs.