Tazobactam was the most recent β-lactamase inhibitor to be approved in 1993. Since the approval of piperacillin–tazobactam, the complexity of β-lactamase–mediated resistance among Gram-negative bacilli has increased enormously. After more than 20 years since the first such combination, amoxicillin–clavulanic acid, was approved, several new β-lactam–β-lactamase inhibitor combinations have reached late-stage (phase II and beyond) clinical trials. These include ceftolozane–tazobactam (2:1, ratios of β-lactam to β-lactamase inhibitor in parentheses), ceftazidime–avibactam (4:1), ceftaroline–avibactam (1:1), and imipenem–cilastatin–MK-7655 (2:2:1 and 4:4:1). Avibactam and MK-7655 are diazabicyclooctane (DABCO) inhibitors and thus not β-lactams themselves; they include class A carbapenemases and class C enzymes within their spectra of activity. Ceftolozane is an antipseudomonal cephalosporin, and tazobactam is used to protect it against extended spectrum β-lactamases to which it is labile. Additional novel combinations are in preclinical development. This review will focus on the biochemistry, antimicrobial activity, pharmacodynamics, and clinical development of these novel combinations.