Purpose of review Although the epidemiology of Clostridioides difficile has changed, this organism continues to cause significant morbidity and mortality. This review addresses current and future approaches to the diagnosis of C. difficile disease. Recent findings Over the last several years, large prospective studies have confirmed that there is no single optimal test for the diagnosis of C. difficile disease. The pendulum has swung from a focus on rapid molecular diagnosis during the years of the ribotype 027 epidemic, to a call for use of algorithmic approaches that include a test for toxin detection. In addition, diagnostic stewardship has been shown to improve test utilization, especially with molecular methods. Advances in testing include development of ultrasensitive toxin tests and an expansion of biomarkers that may be more C. difficile specific. Microbiome research may be leveraged to inform novel diagnostic approaches based on measurements of volatile and nonvolatile organic compounds in stool. Summary As rates of C. difficile infection decline, emphasis is now on improving test utilization and a quest for improved diagnostic approaches. These approaches may involve implementation of technologies that improve toxin testing, predict patients likely to have disease and/or a severe outcome, and harnessing research on changes in the microbiome to advance metabolomics.