The gene Clusterin is a target for cancer therapy in clinical trials. The indication for intervention is up-regulated Clusterin expression. Clusterin has been reported deregulated in multiple cancer types, including colorectal cancer (CRC). However, for CRC the studies have disagreed on whether Clusterin is up- or down-regulated by neoplastic cells. In the present study we sought to clarify the expression and distribution of Clusterin mRNAs and proteins in normal and neoplastic colorectal tissue through laser microdissection, variant specific real-time RT-PCR, immunohistochemistry, immunofluorescence, western blotting, and array based transcriptional profiling. At the transcript level we demonstrated the expression of two novel Clusterin transcripts in addition to the known one, and at the protein level two Clusterin isoforms. Our analysis of normal epithelial cells revealed that in these Clusterin was only expressed by rare neuroendocrine cells. Furthermore, our analysis showed that in the normal mucosa the majority of the observed Clusterin protein originated from the stromal compartment. In tumors we found that Clusterin was de novo synthesized by non-neuroendocrine cancer cells in ~25% of cases. Moreover, we found that the overall Clusterin level in tumors often appeared lower than in normal mucosa due to the stromal compartment often being suppressed in tumors. While Clusterin in normal neuroendocrine cells showed a basal localization, the localization in cancer cells was often apical, and in some cases associated with apical secretion. Collectively, our results indicate that Clusterin expression is very complex. We conclude that Clusterin expression is associated with neuroendocrine differentiation in normal epithelia, and that the Clusterin observed in neoplastic cells is de novo synthesized. The cases with de novo synthesized Clusterin defines a distinct subgroup of CRC that may be of clinical importance as anti-Clusterin therapeutics are now in clinical trials.