Mycobacterial lung infections are caused by Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM). Antimicrobial therapy is the cornerstone of mycobacterial lung infection management. It can be used as a preventive therapy and treatment of active disease. However, the emergence of drug-resistant mycobacteria and the use of suboptimal regimens to treat mycobacterial lung infections jeopardize the ability to treat these infections. Therefore, understanding the different mechanisms causing antimicrobial resistance and optimizing new drugs or regimens to fight drug-resistant bacteria are key to treat effectively lung infections caused by mycobacteria. In this talk, I will discuss the current pre-clinical strategies we have used to find and assess the efficacy of new drugs and regimens for treating Tuberculosis and NTM pulmonary disease, including the difficult-to-treat Mycobacterium abscessus