Fire is being prescribed and used increasingly to promote ecosystem restoration (e.g., oak woodlands and savannas) and to manage wildlife habitat in the Central Hardwoods and Appalachian regions, USA. However, questions persist as to how fire affects hardwood forest communities and associated wildlife, and how fire should be used to achieve management goals. We provide an up-to-date review of fire effects on various wildlife species and their habitat in the Central Hardwoods and Appalachians. Documented direct effects (i.e., mortality) on wildlife are rare. Indirect effects (i.e., changes in habitat quality) are influenced greatly by light availability, fire frequency, and fire intensity. Unless fire intensity is great enough to kill a portion of the overstory, burning in closed-canopy forests has provided little benefit for most wildlife species in the region because it doesn’t result in enough sunlight penetration to elicit understory response. Canopy reduction through silvicultural treatment has enabled managers to use fire more effectively. Fire intensity must be kept low in hardwoods to limit damage to many species of overstory trees. However, wounding or killing trees with fire benefits many wildlife species by allowing increased sunlight to stimulate understory response, snag and subsequent cavity creation, and additions of large coarse woody debris. In general, a fire-return interval of 2 yr to 7 yr benefits a wide variety of wildlife species by providing a diverse structure in the understory; increasing browse, forage, and soft mast; and creating snags and cavities. Historically, dormant-season fire was most prevalent in these regions, and it still is when most prescribed fire is implemented in hardwood systems as burn-days are relatively few in the growing season of May through August because of shading from leaf cover and high fuel moisture. Late growing-season burning increases the window for burning, and better control on woody composition is possible. Early growing-season fire may pose increased risk for some species, especially herpetofauna recently emerged from winter hibernacula (April) or forest songbirds that nest in the understory (May to June). However, negative population-level effects are unlikely unless the burned area is relatively large and early growing-season fire is used continually. We did not find evidence that fire is leading to population declines for any species, including Endangered Species Act (ESA)-listed species (e.g., Indiana bat [Myotis sodalis Mill. Allen] or northern long-eared bat [M. septentrionalis Trouess.]). Instead, data indicate that fire can enhance habitat for bats by increasing suitability of foraging and day-roost sites. Similarly, concern over burning and displacement of woodland salamanders (Plethodontidae), another taxa of heightened conservation concern, is alleviated when fire is prescribed along ecologically appropriate aspect and slope gradients and not forced into mesic, high site index environments where salamanders are most common. Because topography across the Central Hardwoods and Appalachians is diverse, we contend that applying fire on positions best suited for burning is an effective approach to increase regional landscape heterogeneity and biological diversity. Herein, we offer prescriptive concepts for burning for various wildlife species and guilds in the Central Hardwoods and Appalachians.