Use of antibiotics as a therapeutic measure is the most used method for the treatment of infectious diseases including in fisheries and aquaculture. The successful use of any antibiotic in aquaculture is compromised due to the emergence of antimicrobial resistance in bacteria. Bacteria may be intrinsically resistant to different antimicrobial agents or they may acquire resistance through horizontal gene transfer. A number of biochemical and physiological mechanisms are responsible for the development of this resistance. Antimicrobial resistance developed in one ecological niche can spread to another ecological niche and finally can reach the human resulting in a number of treatment failures and high life threatening diseases. The unregulated use of antimicrobial agents has led to the development of antimicrobial resistant fish pathogens as well as other aquatic bacteria. The resistance has been observed in a number of bacterial species including Aeromonas hydrophila, A. salmonicida, Yersinia ruckeri, Edwardsiella tarda, E. ictaluri, Vibrio anguillarum, V. salmonicida, Photobacterium damselae. Multidrug-resistant strains of A. salmonicida and Vibrio harveyi have been reported from different parts of the country. The residues of antimicrobial agents also possess a threat to human health causing allergy, toxicity, alterations of the intestinal flora etc. Antibiotic residues represents potential health hazard and also affects the trade prospects. In this critical scenario different alternative approach can play a crucial role, such as Probiotics, prebiotics and synbiotics, immunostimulants, bacteriophage therapy, vaccine, RNA interference, quorum sensing inhibition etc. All this alternative measures can be used as prophylactic or control measure for fish disease management without hampering the environment. Vaccination is one of the most promising alternatives for the disease management which is being already in use in so many countries. There is every day increasing research in this field of antimicrobial alternatives measures and there are many success stories in the lab as well as in the field also. So days are coming when we can proudly say no to antibiotic use in aquaculture.