(A) Inactivation of ErbB signaling by monoclonal antibodies. Binding of antibody to EGFR may cause receptor internalization and degradation (i). An ErbB-specific antibody may sterically block receptor dimerization (ii). The use of two anti-ErbB antibodies may produce a synergistic effect to inhibit ErbB-mediated signaling and transformation in a more complete manner (iii). (B) The ErbB-specific TKIs target the ATP-binding site of the tyrosine kinase domain of the receptor and directly inhibit ErbB receptor kinase activity. These small molecules can be used either as a single agent (i) or in combination (ii). The pan-specific ErbB-targeted TKI can simultaneously target multiple ErbB receptors (iii). (C) Mechanisms of resistance to ErbB-targeted therapy. ErbB-targeted therapeutics cause downregulation of the MAPK, mTOR, and PI3K signaling pathways (dashed lines indicate reduction of signaling). Resistance may arise in tumor cells through allelic and adaptive changes, leading to activation of PI3K through other receptor tyrosine kinases (RTKs). In this issue of the JCI, Guix et al. (10) demonstrate that downregulation of IGFBP-3 and -4, negative regulators of IGF-IR signaling, causes activation of IGF-IR and the PI3K-Akt pathway and contributes to the resistance of human squamous carcinoma cells to the EGFR inhibitor gefitinib. The heterotetramer of IGF-IR has been simplified in this schematic representation.