Is selection relevant in the evolutionary emergence of drug resistance?

•We argue that the strength of selection can be a poor predictor of the emergence of drug resistance.•Drug resistance can emerge when selected against and can fail to emerge when under positive selection.•We suggest that the absolute fitness of drug-resistant strains is a more relevant predictor of emergence.•We argue that the within-host ecology, and how this is affected by drug pressure, is a primary determinant of absolute fitness.•We demonstrate how within-host ecology can be tied to the familiar MSW hypothesis.

The emergence of drug-resistant pathogens is often considered a canonical case of evolution by natural selection. Here we argue that the strength of selection can be a poor predictor of the rate of resistance emergence. It is possible for a resistant strain to be under negative selection and still emerge in an infection or spread in a population. Measuring the right parameters is a necessary first step toward the development of evidence-based resistance-management strategies. We argue that it is the absolute fitness of the resistant strains that matters most and that a primary determinant of the absolute fitness of a resistant strain is the ecological context in which it finds itself.