There is an upsurge in the resistance pattern of bacterial pathogens demanding new therapeutic targets to keep in pace with the infectious organisms. This review discusses harnessing the virulence factors of microorganisms as drug targets that are produced to cope with demanding and rapidly changing environments during establishment in the host. It would be promising to develop small molecule inhibitors targeting specifically the stress proteins, so-called molecular chaperones that assist the protein folding machinery. There are several natural products that bind specifically to components of the chaperone machinery of microbial pathogens have been identified. Many successful pathogens have developed robust haperone systems to conquer the stressful environments in the host environmental challenges, such as oxidative bursts that are often triggered in response to infection. Heat shock proteins are also linked for the emergence of drug resistance and hence targeting sites unique to the bacterial pathogens can be exploited for therapy, chaperons are already viewed as targets for many human ailments like protein aggregation diseases and cancer. This review discusses new insights in exploiting bacterial chaperones as drug targets and their role in pathogenicity.