OBJECTIVE To describe the mechanisms and clinical relevance of emergent resistance to three recently introduced beta-lactamase inhibitor combinations (BLICs) active against resistant Gram-negative organisms: ceftolozane-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam. RESULTS Despite their recent introduction into practice, clinical reports of resistance to BLICs among typically susceptible organisms have already emerged, in some cases associated with therapeutic failure. The resistance mechanisms vary by agent, including mutations in beta-lactamase active sites, upregulation of efflux pumps, and alterations in the structure or expression of porin channels. These changes may confer cross-resistance or, rarely, increased susceptibility to related agents. Clinicians need to be aware of the potential for initial or emergent resistance to BLICs and ensure appropriate antimicrobial susceptibility testing is performed. Dose optimization and novel combinations of agents may play a role in preventing and managing resistance. Recently approved BLICs have provided important new therapeutic options against resistant Gram-negative organisms, but are already coming up against emergent resistance. Awareness of the potential for resistance, early detection, and dose optimization may be important in preserving the utility of these agents.