Although surgical resection of the solid tumor component of glioblastoma has been shown to provide a survival advantage, it will never be a curative procedure. Yet, systemically applied adjuvants (radiation therapy and chemotherapy) also are not curative and their options are limited by the inability of most agents to cross the blood-brain barrier. Direct delivery of adjuvant therapies during a surgical procedure potentially provides an approach to bypass the blood-brain barrier and effectively treat residual tumor cells. This article summarizes the approaches and therapeutics that have been evaluated to date, and challenges that remain to be overcome.