Several chemotherapeutic agents applied to human beings for past few decades for different ailments, have been found to possess potent antitubercular activity. Two such agents, methdilazine (Md) and promethazine (Pz) were used to select mycobacterial mutants resistant to themselves at different levels and tested to determine if such mutants simultaneously developed cross-resistance to known antitubercular drugs. Mutants were produced by application of a heavy inoculum on Lowenstein-Jensen medium containing Md (or Pz) at concentrations higher than their respective minimum inhibitory concentrations (MICs). These were then tested to find out if such mutants have changed their resistogramme pattern with respect to the test antitubercular agents. Certain first-step Md-mutants became simultaneously resistant to ethambutol and pyrazinamide; while the step-2 Md-mutants revealed further increase in resistance to these agents along with resistance to isoniazid, rifampicin and streptomycin as well. In the study with Pz it was noted that many mutants showed distinctly higher levels of resistance to all the test drugs, particularly to isoniazid, pyrazinamide and streptomycin. The levels of MIC were distinctly high in many mutants. These observations on cross-resistances seem to be best explained on the basis of a reduction in cell-membrane permeability acting in a non-specific manner. The role of such a cross-resistance may possibly be accounting for an overall increase in the MICs of many drugs against several groups of microorganisms including Mycobacterium tuberculosis and other species of Mycobacterium during the last five decades.