Overactivation of epidermal growth factor receptor (EGFR) signaling has been recognized as an important step in the pathogenesis and progression of multiple forms of cancer of epithelial origin. This knowledge has led to a surge of interest in novel anticancer therapies targeting key constituents of the EGFR signal transduction pathway. Several molecular strategies have been developed recently to modulate either EGFR or the downstream signal beyond the cell surface receptor. The important role of aberrant EGFR signaling in the progression of malignant gliomas makes EGFR-targeted therapies of particular interest in this form of cancer. The use of anti-EGFR therapies against malignant brain tumors, although in its infancy, promises to yield exciting results as these new drugs probably will enhance the usefulness of existing therapies.