Bacterial pathogens resistant to multiple structurally distinct antimicrobial agents are causative agents of infectious disease, and they thus constitute a serious concern for public health. Of the various bacterial mechanisms for antimicrobial resistance, active efflux is a well-known system that extrudes clinically relevant antimicrobial agents, rendering specific pathogens recalcitrant to the growth-inhibitory effects of multiple drugs. In particular, multidrug efflux pump members of the major facilitator superfamily constitute central resistance systems in bacterial pathogens. This review article addresses the recent efforts to modulate these antimicrobial efflux transporters from a molecular perspective. Such investigations can potentially restore the clinical efficacy of infectious disease chemotherapy.