Irrational antibiotic usage has led to vast spread resistance to available antibiotics, but we refuse to slide back to “preantibiotic era.” The threat is serious with the “Enterococcus, Staphylococcous, Klebsiella, Acinetobacter, Pseudomonas and Enterobacter” organisms causing nosocomial infections that are difficult to treat because of the production of extended spectrum β-lactamases, carbapenamases and metallo-β-lactamases. Facing us is a situation where soon multidrug resistance would have spread across the globe with no antibiotics to withstand it. The infectious disease society of America and Food and Drug Administration have taken initiatives like the 10 × ‘20 where they plan to develop 10 new antibiotics by the year 2020. Existing classes of antibiotics against resistant bacteria include the carbapenems, oxazolidinones, glycopeptides, monobactams, streptogramins and daptomycin. Newer drugs in existing classes of antibiotics such as cephalosporins, aminoglycosides, tetracyclines, glycopeptides and β-lactamase inhibitors continue to get synthesized. The situation demands newer targets against bacterial machinery. Some of them include the peptidoglycantransferase, outer membrane protein of Pseudomonas, tRNA synthase, fatty acid synthase and mycobacterial ATP synthase. To curb the irrational and excessive usage of presently available antibiotics should be a priority if they are still to be kept in usage for the future.