The initial period of studies on Clostridium difficile (published during 1978-1980) appeared to provide a nearly complete portfolio of criteria for diagnosing and treating C. difficile infection (CDI). The putative pathogenic role of C. difficile was established using Koch's postulates, risk factors were well-defined, use of a cell cytotoxicity assay as the diagnostic test provided accurate results, and treatment with oral vancomycin was highly effective and rapidly incorporated into practice. During the next 10 years, enzyme immunoassays (EIAs) were introduced as diagnostic tests and became the standard for most laboratories. This was not because EIAs were as good as the cell cytotoxicity assay; rather, EIAs were inexpensive and yielded results quickly. Similarly, metronidazole became the favored treatment because it was less expensive and quelled fears of colonization with vancomycin-resistant organisms, not because it was better than vancomycin therapy. Cephalosporins replaced clindamycin as the major inducers of CDI because they were so extensively used, rather than because they incurred the same risk. Some serious issues remained unresolved during this period: the major challenges were to determine ways to treat seriously ill patients for whom it was not possible to get vancomycin into the colon and to find methods that stop persistent relapses. These concerns persist today.