The emergence of drug resistance in many bacterial pathogens and the rise of fungal infections have caused a resurgence of interest in finding new reserves of bioactive compounds. The increase in resistance to conventional antibiotics by many bacterial pathogens may be due to the decline in the discovery and development of novel antibiotics. Superbugs are those microorganisms (pathogens) that are resistant to the commonly used antibiotics. The World Health Organisation (WHO) has published a list of twelve potentially most dangerous priority pathogens with antibiotic resistance in 2017 and emphasized on discovering new antibiotics to tackle these pathogens. ESKAPE pathogens comprising Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa and, Enterobacter species can productively escape the antagonistic effects of the current antimicrobial agents. Urgent discovery of new drugs to tackle these resistant pathogens is required. This chapter mainly focuses on the strategies and methods on discovering novel antibiotics against drug resistant pathogens.