Historical reports about carpal tunnel syndrome (CTS) exist from its first description in 1854 to current developments. Although now a well-recognized entity, it took nearly 100 years from its initial description before accurate pathophysiology was determined and agreed upon by the medical community. Along the way, many individuals have contributed to our present understanding of CTS. Stumbling blocks have included a delay of many years for accurate anatomical localization, as well as incorrect initial surgical treatment selection without scientific basis. By the middle of the 20th century, the standard of care for CTS had reached the standard of our modern era, based on scientific study and documentation. By the latter half of the 20th century, pathophysiology had been established, diagnostic signs and testing had been well evolved, and surgical techniques had become refined. Emerging frontiers being explored from the late 20th century into the new millennium include and incorporate advances in diagnostic and surgical technology and equipment. Patient demographics have also shown evolution. Controversies continue and more research is needed to establish more definitive criteria as to causation of CTS by various factors, including repetitive stress.