Extracorporeal membrane oxygenation (ECMO) is an emerging treatment modality associated with a high frequency of antibiotic use. However, several covariables emerge during ECMO implementation, potentially jeopardizing the success of antimicrobial therapy. These variables include but are not limited to: the increased volume of distribution, altered clearance, and adsorption into circuit components, in addition to complex interactions of antibiotics in critical care illness. Furthermore, ECMO complicates the assessment of antibiotic effectiveness as fever, or other signs may not be easily detected, the immunogenicity of the circuit affects procalcitonin levels and other inflammatory markers while disrupting the immune system. We provided a review of pharmacokinetics and pharmacodynamics during ECMO, emphasizing practical application and review of patient-, illness-, and ECMO hardware-related factors.