Phenotypic screening seems to be a more promising approach to identify compounds active against MDR-TB than the target-based approach. Despite this, the search for new compounds active against resistant-TB remains a challenge. The molecular mechanism involved in the resistance and its possible targets is still not completely understood. However, even in this complicated scenario, in recent years, active compounds against resistant strains have been found at nanomolar concentrations. In addition, in vivo studies have shown that some of these compounds exhibited adequate pharmacokinetics for investigation in future studies. Additional efforts must be made in order to create strong networks worldwide to discover new drugs against this terrible disease.