Highlights the experiences of patients to examine how diagnostic uncertainty in cystic fibrosis has persisted despite the introduction of new technologies. Using the critical case of cystic fibrosis (CF), Challenging Diagnosis probes the sociocultural and scientific factors that have contributed to diagnostic uncertainty in medicine while foregrounding its impact on patients and families. Though often described in medical and biology texts as a model genetic disease, making it straightforward to identify, diagnosing CF has long been fraught with challenges. As Michelle LaBonte shows, looking at CF illustrates how diagnostic uncertainty has persisted despite—and even because of—new technologies. Drawing on her own experiences as a patient with pancreatic insufficiency, a condition often seen in people with CF, LaBonte examines shifts in CF’s screening and diagnosis, from the first comprehensive descriptions of the disease in the 1930s to contemporary genetic testing for carrier status. Today, the diagnosis of CF is no more straightforward than it was in the mid-twentieth century. Since many diagnostic technologies for CF (or their analogs) have been used throughout medicine, as LaBonte explains, these findings are broadly applicable beyond CF and demonstrate the significant harms associated with relying on test results that prioritize disease specificity over patient narratives. In her historical analysis and her personal story, LaBonte highlights the shortcomings of a reductionist biomedical model that’s overly reliant on diagnostic technologies, a concern that’s more relevant than ever now that direct-to-consumer genetic testing and use of whole genome sequencing in newborns are increasing.