This article analyzes the relationship between demonology and discernment of spirits in sixteenth-century Europe. Discernment was a theoretical and practical device employed to distinguish between spirits (divine, demonic, human). More often than not, as it dealt with pneumatology (the ontology and action of spirits), it was closely coupled with demonological discourse. As the article suggests, however, discernment could also inform epistemological, natural-philosophical, and biblical critiques concerning demonology and its supporters. The Spanish Catholic physician Juan Huarte de San Juan (ca. 1529–88), the English reformed squire Reginald Scot (ca. 1538–99), and the French Catholic physician Michel de Marescot (1539–1606) advanced such positions. A thematic and comparative approach to their works shows their radical emphasis on natural over demonic causality, their instrumentalization of discernment against demonology, their use of biblical passages to support this skeptical stance, and their defense of a lay discernment of spirits.