Pharmaceutical companies have developed targeted therapies such as trastuzumab and lapatinib for human epidermal growth factor receptor (HER)2/neu-positive tumors, while others have developed antiepidermal growth factor receptor (EGFR) therapies, such as tarceva and erbitux for EGFR-positive tumors. A drug called rencarex is targeted to an oncoprotein designated carbonic anhydrase IX (CAIX), which is being evaluated in renal cell carcinoma patients. Based on these targeted therapeutic approaches, this review describes clinical research studies performed with enzyme-linked immunosorbent assays specific for the circulating oncoproteins, HER2/neu, EGFR and CAIX. These circulating biomarkers have the potential to be used in conjunction with the specific targeted therapies for patient selection, monitoring and management. With the variety of new therapeutic options, the major challenge ahead will be to select the appropriate therapy or combinations of therapies for each patient. Specific biomarker tests, either alone or in panels, will be needed at the appropriate time in the course of disease to ensure that patients receive the right drug at the right time. These tests will also be valuable in monitoring the efficacy of the targeted therapies. A circulating biomarker such as serum HER2/neu may be able to specifically identify patients with progressing HER2/neu-positive disease and provide the information needed by physicians to choose from the variety of HER2/neu-targeted therapies that will soon be available to cancer patients.