Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with a C-terminal epoxide hydrolase activity and an N-terminal phosphatase activity. Arachidonic acid epoxides, previously suggested to be involved in apoptosis, oncogenesis and cell proliferation, are generated by cytochrome P450 epoxygenases and are good substrates of the sEH C-terminal domain. In addition, the N-terminal phosphatase domain hydrolyzes isoprenoid mono- and pyrophosphates, which are involved in cell signaling and apoptosis. Here we provide a comprehensive analysis of the distribution of sEH, CYP2C8, 2C9 and 2J2 in human neoplastic tissues using tissue micro-arrays. The human neoplastic tissue micro-arrays provide a well-controlled side by side analysis of a wide array of neoplastic tissues and their surrounding normal tissue controls. Many of the neoplastic tissues showed altered expression of these enzymes as compared to normal tissues. Altered expression was not limited to the neoplastic tissues but also found in the surrounding non-neoplastic tissues. For example, sEH expression in renal and hepatic malignant neoplasms and surrounding non-neoplastic tissues was found to be significantly decreased, whereas expression was found to be increased in seminoma as compared to normal tissues. Our study warrants further investigation of the role of altered expression of these enzymes in neoplastic tissues.