The concept of “cost of resistance” has been very important for decades, for fundamental reasons (theory of adaptation), with a wide range of applications for the genetics and genomics of resistance: resistance to antibiotics, insecticide, herbicide, fungicides; resistance to chemotherapy in cancer research; coevolution between all kinds of parasites and their hosts. This paper reviews this history, including latest developments, shows the interest of the idea but also challenges the usefulness and limits of this widely used concept, based on the most recent development of adaptation theory. It explains how the concept can be flawed and how this can impede research efforts in the field of resistance at large, including all applied aspects. In particular, it would be clearer to simply measure the fitness effects of mutations across environments and to better distinguish those effects from ‘pleiotropic effects’ of those mutations. Overall, we show how to correct the concept, and how this correction helps to better understand the wealth of data that has accumulated in recent years. The main points are:
1. The concept of «cost of resistance» needs to be carefully used, to avoid misconceptions, false paradox and flawed applications. The recent developments in adaptation theory are useful to clarify this.
2. “Cost of resistance” and pleiotropy have to be distinguished. More than one trait is required to discuss pleiotropy. Resistance evolution must at least involve the modification of one trait. If there is an irreducible trade-off on that trait between environments with and without drug, it creates a fitness effect that is not due to pleiotropy. Pleiotropic effects can, but need not, occur in addition.
3. “Cost of resistance” must depend on the pair of environments considered with and without drug. Hence, there are as many measures of cost as there are environments without drug. If the focal genotype is not well adapted to one focal environment, it is relatively easy to observe “negative” costs of resistance. There is nothing surprising about this, and it does not indicate an absence of trade-off.
4. Environments with drug can differ according to the dose. It may be more informative to measure the possible trade-offs among all doses than to focus exclusively on the fitness contrast between the presence and the absence of drug.