The epidermal growth factor receptor (EGFR) is the main tyrosine kinase receptor dysregulated or overexpressed in brain cancer types and its expression is directly correlated with tumor malignancy and unfavorable prognosis. Recently, the availability of endogenous EGFR ligands has been reported to be also regulated indirectly by the activation of several G-protein-coupled receptors (GPCRs) in many cancer cell types. This EGFR transactivation mechanism requires the initial activation of a GPCR that in turn induces the cleavage of membrane-bound EGFR ligands precursors via the involvement of the family of disintegrin and metalloproteases (ADAMs). The discovery of ADAMs in this transactivation mechanism led to the development of small molecule inhibitors. In this minireview we describe the expression of GPCR, ADAMs and EGFR ligands in human glioma brain tumors and the characteristics of small molecule ADAMs inhibitors. The addition of ADAM inhibitors to our pharmacological arsenal could enhance the outcome of combination therapies when using EGFR inhibitors against human brain tumors.