Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults with a high recurrence and mortality rate. GBM tumors contain a high degree of cellular heterogeneity, with cells exhibiting stem-like properties (cancer stem cells; CSCs) that are highly efficient at tumor initiation and are resistant to conventional therapies. CSCs interact with their tumor microenvironment by a large group of diverse cell adhesion molecules (CAMs) that participate in intercellular, intracellular and cell-extracellular matrix interactions. Despite the initial description of CAMs as tumor suppressors, recent work has highlighted specific CAMs that are essential for CSC maintenance and tumor progression. This review will highlight recent findings that provide support for a context-specific role of CAMs in CSC function and GBM progression.