In the past three decades, several drugs have been proved to be highly effective in the therapy of the mycobacterial infections (tuberculosis, leprosy, atypical mycobacteriosis). In spite of these successes, mycobacterial infections are still a world health problem. The search for new antimycobacterial agents is necessary due to the increasing resistance of mycobacteria to the available drugs, the increasing frequency of atypical mycobacteriosis, the unsatisfactory status of leprosy treatment and the various and sometimes serious side effects of the available drugs. Most of the presently used antitubercular agents represent the result of a large screening program leading to the selection of active compounds, followed generally by chemical modification of the selected substances, in order to optimize their therapeutic efficacy. There is no doubt that this approach, so fruitful in the past, will be also followed in the future. In the case of antileprous drugs, their selection was generally done among antitubercular substances, the screening and evaluation tests for antileprous activity being too time consuming. Recent studies on specific constituents of the mycobacterial cell, such as the mycolic acids, the toxic principles (cord factor), the growth factors (mycobactins) and specific enzymes might give the possibility of a rational approach to new antimycobacterial drugs. Also the studies on the mechanism of action of the main drugs already used in therapy and on the mycobacterial resistance to them could possibly give leads for the search for new products overcoming the resistance mechanisms.