It is well known that the Horsley-Clarke frame was developed and first used by Robert Henry Clarke and the pioneer neurosurgeon Victor Horsley in 1906 for making lesions in the central nervous system of animals. The Horsley-Clarke frame was extensively used throughout the next 4 decades for excitation and lesion production in animals. Aubrey Mussen, a student of Clarke, designed a stereotactic apparatus for use in humans, but no procedures were actually performed with the instrument. It is less appreciated that a Horsley-Clarke frame was also constructed for human use and first applied for depth electroencephalography by Robert Hayne and Frederic Gibbs in 1947. The assumed relationship between external landmarks and intracranial structures provided initial target localization, and pneumoencephalography confirmed depth electrode position. In many ways, the work of Hayne and Gibbs paralleled the simultaneous efforts of Ernest A. Spiegel and Henry T. Wycis. Events leading to the development of stereotactic frames and their subsequent use in humans for the treatment of epilepsy, movement disorders, and psychosurgery are reviewed.