The role of stem cells in solid tumors remains controversial. In colorectal cancers (CRC), this is complicated by the conflicting ‘top-down’ or ‘bottom-up’ hypothesis of cancer initiation. We profiled the expressions of genes from the top (T) and bottom (B) fractions of the crypt in morphologically normal-appearing colonic mucosa (M) and contrasted this to that of matched mucosa adjacent to tumors (MT) in twenty three sporadic CRC patients. In thirteen patients, the genetic distance (M-MT) between the B fractions is smaller than the distance between the T fractions indicating that the expressions of significant genes diverge further in the top fractions (BT). Taking genetic divergence as an intermediate endpoint, the data indicates that it is equally likely that CRC initiates from ‘top-down’ via dedifferentiated colonocytes or ‘bottom-up’ via dysregulated intestinal stem cells. This has important ramification for subsequent therapeutic considerations. Overall design: Total RNA from 23 sporadic CRC patients matched mucosa (M) and mucosa next to tumor (MT) top and bottom crypt fractions were profiled with Affymetrix GeneChip human gene 1.0 ST array. The genetic distance between M and MT (M-MT) for 80 significantly differentially expressed genes were calculated for both top and bottom fractions. The genetic distance (M-MT) for the top (T) fractions were compared to the bottom (B) fractions for every patient to decide whether the divergence is greater in the bottom fraction (B >T) or top (B