An understanding of the microecology of Clostridium difficile provides for a better understanding of the disease that this organism causes. C. difficile is not a significant component of the microflora in the colon of healthy adult humans or animals; however, it can establish large populations in antibiotic-treated or gnotobiotic animals and in infants before they acquire a complete flora. Major factors that determine whether or not disease develops are: (1) the size of the C. difficile populations; (2) the toxigenicity of the colonizing strain; (3) the presence of other organisms that affect toxin expression or activity; (4) susceptibility of the host; and possibly (5) a strain's adhesion to colonic epithelium. The rest of the colonic flora determines the size of the C. difficile population, at least in part by limiting available nutrients. In outbreaks, most C. difficile disease is caused by nosocomial strains. Environmental contamination with spores and spread via the hands of health care workers have been implicated in transmission. Information with regard to this organism's microecology suggests alternative approaches to the control of disease.