Here, we describe the epidemiology, diagnostics, and treatment of Clostridioides difficile infection (CDI) in the primary health care setting. CDI is traditionally considered as a healthcare associated infection. However, infections with onset in the community represent a large proportion of CDI. Traditional CDI risk factors apply to the population encountered in general practice: age ≥50 years, malignancy or other underlying disease, hospital admission and/or antibiotic treatment in the past 3 months. Notably, about a third has had no recent antibiotic exposure nor has been admitted to a hospital. Based on diagnostic tests requested by the general practitioner, only half of CDI cases will be diagnosed. In this setting, it is advisable to request a diagnostic C. difficile test for patients with persisting or severe diarrhea and negative tests for traditional enteropathogens (Salmonella, Shigella, Yersinia, Campylobacter), also in the absence of traditional risk factors for CDI.