Signal transduction pathways regulated by the EGFR/ERBB/HER proto-oncogene family and receptor tyrosine kinases encoded by these genes are known to become dysregulated during cellular transformation and carcinogenesis. Consequently, biologically targeted antibodies and tyrosine kinase inhibitors directed toward EGFR/ErbB1/HER1 (eg, cetuximab, erlotinib and gefitinib) and ErbB2/HER2 (eg, trastuzumab), and more recently toward ErbB3/HER3 and ErbB4/HER4, are being investigated as therapeutic agents for treating patients with EGFR/ERBB/HER proto-oncogene-driven malignancies. The accurate selection of patients who will respond efficaciously to these agents a priori is a medical challenge. Understanding the clinical utility of soluble EGFR/ErbB/HER (ie, sEGFR/sErbB/sHER) isoforms, which are present in circulatory fluids, as theragnostic cancer biomarkers is an emerging area of contemporary biomedical investigation. This feature article reviews the literature regarding the clinical utility of serum sEGFR/sErbB1/sHER1 in breast, lung and ovarian cancer, and discusses the potential role of sEGFR in predicting and monitoring therapeutic responsiveness, as well as disease recurrence, and/or predicting disease outcome in patients treated with specific small-molecule, hormonal or biotherapeutic drug regimens. Well-designed translational research studies are needed to validate sEGFR as a theragnostic biomarker further and to achieve routine clinical implementation.