The current crisis in bacterial antibiotic resistance can be attributed to the overuse (or misuse) of these essential medicines in healthcare and agriculture, coupled with the slowed progression of new drug development. In the versatile, opportunistic pathogen , the Resistance-Nodulation-Division (RND) efflux pump MexXY plays critical roles in both cell physiology and the acquisition of multidrug resistance. The operon is not constitutively expressed, but this process is instead controlled by a complex network of multiple interconnected regulatory mechanisms. These include induction by several of the pump's ribosome-targeting antibiotic substrates and transcriptional repression and anti-repression processes that are themselves influenced by various cellular factors, processes, or stresses. Although extensive studies of the MexXY complex are currently lacking as compared to other RND efflux pumps such as AcrAB-TolC, recent studies have provided valuable insights into the MexXY architecture and substrate profiles, including its contribution to clinical resistance. Furthermore, while MexXY primarily associates with the outer membrane protein OprM, emerging evidence suggests that this transporter-periplasmic adaptor pair may also partner with other outer membrane proteins, potentially to alter the efflux substrate profile and activity under specific environmental conditions. In this minireview, we summarize current understanding of MexXY regulation, structure, and substrate selectivity within the context of clinical resistance and as a framework for future efflux pump inhibitor development.