The Hippo signaling pathway is a highly conserved potent regulator of cell growth, division, and apoptosis. Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a highly conserved component of this pathway in mammalian systems. In humans, amplification of the chromosome region containing the YAP gene (11q22) has been reported in several tumor types. This study was performed to determine if YAP expression was present in 4 common types of malignant tumors that have the highest lifetime risk of causing cancer death among men and women in the United States. The YAP expression intensity and distribution were evaluated in normal tissues and compared to the most frequently occurring malignant tumors in these tissues (colonic adenocarcinoma, lung adenocarcinoma, ovarian serous cystadenocarcinoma, and ductal carcinoma of the breast). For each tissue, the nuclear and cytoplasmic YAP expression intensity was scored as negative, low, or high. We found focal expression of YAP in the progenitor and reparative cellular compartments of normal tissue. In contrast, there was strong and diffuse nuclear and cytoplasmic YAP expression in colonic adenocarcinoma, lung adenocarcinoma, and ovarian serous cystadenocarcinoma. We concluded that the potent Hippo growth regulatory pathway shows markedly different expression patterns in normal tissues of the colon, lung, and ovary compared to the 3 common malignant tumor types we examined in these tissues. Our findings suggest that activation of the Hippo signaling pathway may occur through YAP as part of cell proliferation in normal tissue homeostasis and also might be a frequently activated oncogenic pathway in 3 common malignant tumor types.