The cost of prescription drugs in the United States is rising like never before and has led to an inflection point where clinicians must consider the potential financial damage to the patient and to society related to the more expensive drugs available. Many of the highest-priced drugs are approved as orphan drugs, a legally defined status providing additional benefits to pharmaceutical companies that is intended to incentivize therapeutic development for rare diseases. The Orphan Drug Act has been a great success since it was enacted in 1983, resulting in the development of many innovative, life-changing, and even lifesaving drugs; however, high drug prices place patients at risk for personal bankruptcy, prescription abandonment, and higher rates of hospitalization. These negative consequences have become more widespread and severe because some companies exploit pricing via the market exclusivity granted to them under the provisions of the Orphan Drug Act. As more and more companies develop these drugs, the cost to society increases as does the capacity to tolerate unjustified prices. The societal effects of drug pricing must be considered through the prism of opportunity costs; that is, what benefit is lost by choosing to spend on one thing instead of another. Clinical- and economic-based analyses from independent groups such as the Institute for Clinical and Economic Review can help physicians understand the value of drugs (ie, the benefits relative to cost). When prescribing a high-priced medication, clinicians should discuss the drug's value and the associated opportunity cost with patients and have an open discussion about patients' ability to financially tolerate the treatment.