Antibiotic resistance has emerged as an important determinant of mortality for patients in the intensive care unit (ICU) setting. This is largely due to the increasing presence of pathogenic microorganisms with resistance to existing antibiotic agents, resulting in the administration of inappropriate treatment. Escalating antibiotic resistance has also been associated with greater overall health care costs, as a result of prolonged hospitalizations and convalescence associated with failure of antibiotic treatment, the need to develop new antibiotic agents, and the implementation of broader infection control and public health interventions aimed at curbing the spread of antibiotic-resistant pathogens. Antibiotic cycling has been advocated as a tool to reduce the occurrence of antibiotic resistance, especially in the ICU setting. Unfortunately, the cumulative evidence to date suggests that antibiotic cycling has limited efficacy for preventing antibiotic resistance. Nevertheless, a strategy whereby multiple or all classes of antibiotics are available for use (i.e., antibiotic heterogeneity) can be part of a broader effort aimed at curtailing antibiotic resistance within ICUs. Such efforts should be routine, given the limited availability of new antibiotic drug classes for the foreseeable future.