Background. Despite curative surgery, prognosis of esophageal cancer is still poor. The aim of our study was to define the (co-)expression pattern of target receptor-tyrosine-kinases (RTK) and to evaluate the role of chemokine receptor CXCR4 in esophageal adenocarcinoma and squamous cell cancer. Methods. The (co-)expression pattern of VEGFR1-3, PDGFR alpha/beta and EGFR1 was analyzed by RT-PCR in 50 human esophageal cancers (35 adenocarcinomas and 15 squamous cell cancers). In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation. In 102 consecutive patients undergoing esophageal resection for cancer, the LSAB+ system was used to detect the protein CXCR4. Tumor samples were classified into two groups based on the homogeneous staining intensity (weak and strong CXCR4 expression). Results. Adenocarcinoma samples revealed a VEGFR1 (97%), VEGFR2 (94%), VEGFR3 (77%), PDGFR alpha (91%), PDGFR beta (86%) and EGFR1 (97%) expression at different intensities. 94% of esophageal adenocarcinomas expressed at least four out of six RTKs. Similarly, squamous cell cancers revealed a VEGFR1 (100%), VEGFR2 (100%), VEGFR3 (53%), PDGFR alpha (100%), PDGFR beta (87%) and EGFR1 (100%) expression at different intensities. All esophageal squamous cell carcinomas expressed at least four out of six RTKs. With regard to CXCR4 expression, in adenocarcinoma, a rate of 89.1% was detected with a weak intensity in 71.7% compared to strong staining in 29.3%. The overall expression rate for CXCR4 in esophageal squamous cell carcinoma was 94.1%, subdivided into 54.9% with weak and 45.1% with strong staining. Conclusion. Our results reveal a high rate of receptor-tyrosine-kinases (co-) expression and expression of chemokine receptor CXCR4 in esophageal adenocarcinoma and squamous cell cancer and might therefore encourage an application of multiple-target RTK-inhibitors as well as of CXCR4-antagonists within a multimodal concept as a promising novel approach for innovative treatment strategies.