Natural Antimicrobial peptides (AMPs) are important components of immune systems and possess immuno-modulatory and broad spectrum antimicrobial activities. These host-defense peptides failed to resist protease degradation or to efficiently inhibit biofilm formation. We describe in this review the different strategies to improve AMPs and develop peptides that could be used clinically and in industry through antimicrobial, antibiofilm and/or anti-inflammatory activities, protease resistant property and without being cytotoxic. They can be developed as free molecules or immobilized on surfaces or in synergy with other treatments. AMPs could be the next important step in bacteriology treatment after antibiotic discovery.