Cell envelope–active agents, particularly β-lactams, play a pivotal role in the treatment of bacterial infections and the extent to which their activity is affected by the emergence of multidrug-resistant organisms is of concern. We analyzed the Surveillance Network (TSN) database to evaluate resistant trends for key cell envelope–active drugs among ESKAPE pathogens. Analysis demonstrated that the activity of these drugs has been notably influenced by the emergence of multidrug resistance; this was especially evident for the β-lactam drugs. For example, Acinetobacter baumannii resistance to imipenem increased from 23.9% to 34.3%, and resistance to piperacillin–tazobactam increased from 37.0% to 49.7% between 2007 and 2011. During the same time period Klebsiella pneumoniae resistance to imipenem increased from 0.8% to 3.8%. As β-lactams are a cornerstone of anti-infective therapy, it is important to closely monitor the activity of the agents being used today and to aggressively pursue new strategies that can augment current drugs and thwart ever-emerging β-lactam resistance mechanisms that are continuously encountered.