Salmonellae have evolved a wide range of molecular mechanisms to neutralize the effect of antibiotics and evade the host immune system response. These mechanisms are exquisitely controlled by global and local regulators and enable the pathogens to use its energy as per need and hence allow the pathogen to economize the consumption of energy by its cellular machinery. Several families that regulate the expression of different drug resistance genes are known; some of these are: the TetR family (which affects tetracycline resistance genes), the AraC/XylS family (regulators that can act as both transcriptional activators and repressors), two-component signal transduction systems (e.g. PhoPQ, a key regulator for virulence), mercury resistance Mer-R and multiple antibiotic resistance Mar-R regulators, LysR-type global regulators (e.g. LeuO) and histone-like protein regulators (involved in the repression of newly transferred resistance genes). This minireview focuses on the role of different regulators harbored by the Salmonella genome and characterized for mediating the drug resistance mechanisms particularly via efflux and influx systems. Understanding of such transcriptional regulation mechanisms is imperative to address drug resistance issues in Salmonella and other bacterial pathogens.