Context.-Relatively little is known about the significance and potential impact of glass-digital discordances, and this is likely to be of importance when considering digital pathology adoption. Objective.-To apply evidence-based medicine to collect and analyze reported instances of glass-digital discordance from the whole slide imaging validation literature. Design.-We used our prior systematic review protocol to identify studies assessing the concordance of light microscopy and whole slide imaging between 1999 and 2015. Data were extracted and analyzed by a team of histopathologists to classify the type, significance, and potential root cause of discordances. Results.-Twenty-three studies were included, yielding 8069 instances of a glass diagnosis being compared with a digital diagnosis. From these 8069 comparisons, 335 instances of discordance (4%) were reported, in which glass was the preferred diagnostic medium in 286 (85%), and digital in 44 (13%), with no consensus in 5 (2%). Twenty-eight discordances had the potential to cause moderate/severe patient harm. Of these, glass was the preferred diagnostic medium for 26 (93%). Of the 335 discordances, 109 (32%) involved the diagnosis or grading of dysplasia. For these cases, glass was the preferred diagnostic medium in 101 cases (93%), suggesting that diagnosis and grading of dysplasia may be a potential pitfall of digital diagnosis. In 32 of 335 cases (10%), discordance on digital was attributed to the inability to find a small diagnostic/prognostic object. Conclusions.-Systematic analysis of concordance studies reveals specific areas that may be problematic on whole slide imaging. It is important that pathologists are aware of these areas to ensure patient safety.