Strains of bacterial pathogens that have acquired mutations conferring antibiotic resistance often have a lower growth rate and are less invasive or transmissible initially than their susceptible counterparts. However, fitness costs of resistance mutations can be ameliorated by secondary site mutations. These so-called compensatory mutations may restore fitness in the absence and/or presence of antimicrobials. We review literature data and show that the fitness gains in the absence and presence of antibiotic treatment need not be correlated. The aim of this study is to gain a better conceptual grasp of how compensatory mutations with different fitness gains affect evolutionary trajectories, in particular reversibility. To this end, we developed a theoretical model with which we consider both a resistance and a compensation locus. We propose an intuitively understandable parameterization for the fitness values of the four resulting genotypes (wild type, resistance mutation only, compensatory mutation only, and both mutations) in the absence and presence of treatment. The differential fitness gains, together with the turnover rate and the mutation rate, strongly affected the success of antibacterial treatment, reversibility, and long-term abundance of resistant strains. We therefore propose that experimental studies of compensatory mutations should include fitness measurements of all possible genotypes in both the absence and presence of an antibiotic.The global rise of antimicrobial resistance in bacteria, combined with the decreasing number of innovative antibacterial agents, has led to warnings that we may soon lose our ability to treat bacterial infections (82). This spread of strains that are genetically resistant is occurring despite the fact that resistance is often costly. When resistance is due to an altered target, this target might not work as well as its progenitor. Efflux pumps or bacterial enzymes that modify the antibiotic often lead to metabolic costs (1). This fitness loss may be reflected in a reduced growth rate in vivo (e.g., see reference 51) or in vitro (reviewed in references 3 and 85), a reduced transmission rate (66), a higher clearance rate (29), or decreased invasiveness (22) in the absence of antibiotics. The costs of resistance are among the most important factors determining both the rate and extent of resistance emergence (2,3,15,32,44,50). In order to devise strategies to contain antibacterial resistance, we therefore need to predict the fitness trajectories (i.e., how the fitness of a strain will change over time) of resistant strains and to investigate whether and how resistance may be reversible once it has emerged. Antimicrobial-induced killing or growth suppression does not necessarily increase monotonically with drug concentration. Therefore, it is not always clear how the MIC and the growth rate at a defined concentration are correlated. Rather than making assumptions about the fitness landscape, in the following material we take the growth rate at therapeutic concentrations ...