Diagnostic errors have been deemed the "next frontier" in patient safety based on studies suggesting their significant contribution to patient harm. While prevention strategies have focused on the acute care setting, equal concern about diagnostic errors is warranted in primary care practices. This multicenter study surveyed more than 1000 primary care physicians who reported that more than 5% of their patients were difficult to diagnose. Inadequate knowledge was the most commonly reported cognitive factor, with more experienced physicians reporting less diagnostic difficulty. Addressing workload issues, such as panel size and non-visit tasks, was the most common improvement strategy. The authors discuss both system- and practice-level initiatives that may reduce diagnostic difficulties, including allowing more time to process diagnostic information and facilitating better subspecialty input. A past AHRQ WebM&M perspective and interview discuss diagnostic errors.