This article is about risk. Risk is probably the most misunderstood component in determining therapeutic intervention; however, it is probably the most relevant issue to consider in the context of expected benefit. The rarity of quantitative risk–benefit assessment and the lack of comparative risk–benefit when alternative therapies exist for a given condition leads to inadequate decisions. Without some quantitation of the risks associated with specific therapies, doctors and patients cannot make optimal risk–benefit calculations. Patients may abandon effective therapies for which benefits may still outweigh risks, or opt for therapies with less well-publicized potential adverse events of even greater frequency or severity. When only small incremental benefits accrue to patients from the use of a given therapy, on the other hand, even very rare serious events may play a role in decision-making by patients, by their health care providers and by regulatory authorities.