Standard doses of antibiotics do not efficiently treat chronic infections of the soft tissue and bone. In this Personal View, we advocate for improving treatment of these infections by taking the infectious microenvironment into account. The infectious microenvironment can cause sensitive bacteria to lose their susceptibility to antibiotics that are effective in standard laboratory susceptibility testing. We propose that bacteria behave substantially different in standard laboratory conditions than they do in actual infections. The infectious microenvironment could impose changes in growth and metabolic activity that result in increased protection against antibiotics. Therefore, we advocate that improved antibiotic treatment of chronic infection is achievable when antibiotics are recommended on the basis of susceptibility testing in relevant in vitro conditions that resemble actual infectious microenvironments. We recommend establishing knowledge of the relevant conditions of the chemical and physical composition of the infectious microenvironment. Recent advances in RNA sequencing, metabolomics, and microscopy have made it possible for the characterisation of the microenvironment of infections and to validate the clinical relevance of in vitro conditions to actual infections.