Erythromycin A, the first macrolide, was introduced in the 1950s and after years of clinical experience it still remains a commonly relied upon antibiotic. In the past, pharmacodynamic characteristics of macrolides beyond antimicrobial action such as anti-inflammatory and immune-modulating properties have been of scientific and clinical interest. The function of erythromycin as a prokinetic agent has also been investigated for a range of gastrointestinal motility disorders and more recently within the context of critically ill patients. Prokinetic agents are drugs that increase contractile force and accelerate intraluminal transit. Whilst the anti-inflammatory action may be a desirable side effect to its antibiotic action, using erythromycin A merely for its prokinetic effect alone raises the concern about promoting emergence of macrolide resistance. The objectives of this review article are: (i) to briefly summarize the modes and epidemiology of macrolide resistance, particularly in respect to that found in the Streptococcus species (a potential reservoir for the dissemination of macrolide resistance on the critical care unit); (ii) to discuss in this context the evidence for conditions promoting bacterial resistance against macrolides; and (iii) to assess the potential clinical benefit of using erythromycin A as a prokinetic versus the risks of promoting emergence of macrolide resistance in the clinical setting. We conclude, that in view of the growing weight of evidence demonstrating the potential epidemiological impact of the increased use of macrolides upon the spread of resistance, versus a lack of sufficient and convincing evidence that erythromycin A is a superior prokinetic agent to potential alternatives in the critically ill patient population, at this stage we do not advocate the use of erythromycin A as a prokinetic agent in critically ill patients unless they have failed all other treatment for impaired gastrointestinal dysmotility and are intolerant of metoclopramide. Further large and methodologically robust studies are needed to ascertain the effectiveness of erythromycin A and other alternative agents in the critically ill.