Increasing incidence of resistance of gram-negative bacteria against even newer antibiotic including carbapenem has generated interest in the old antibiotic colistin, which are being used as salvage therapy in the treatment of multidrug resistant infection. Colistin has excellent bactericidal activity against most gram-negative bacilli. It has shown persist level in the liver, kidney, heart, and muscle; while it is poorly distributed to the bones, cerebrospinal fluid, lung parenchyma, and pleural cavity. Being an old drug, colistin was never gone through the drug development process needed for compliance with competent regulatory authorities that resulted in very much limited understanding of pharmacokinetic (PK) and pharmacodynamic (PD) parameters, such as C max/MIC ratio, AUC/MIC and T > MIC that could predict the efficacy of colistin. In available PK/PD studies of colistin, mean maximum serum concentration (C max) of colistin were found just above the MIC breakpoint at steady states that would most probably lead to suboptimal for killing the bacteria, even at dosages of 3.0 million international units (MIU) i.e., 240 mg of colistimethate sodium (CMS) intravenously every 8 h. These finding stresses to use high loading as well as high maintenance dose of intravenous colistin. It is not only suboptimal plasma concentration of colistin but also poor lung tissue concentration, which has been demonstrated in recent studies, poses major concern in using intravenous colistin. Combination therapy mainly with carbapenems shows synergistic effect. In recent studies, inhaled colistin has been found promising in treatment of lung infection due to MDR gram-negative bacteria. New evidence shows less toxicity than previously reported.