Methods, biomarkers, and expression signatures are disclosed for assessing the regulation status of Wnt/.beta.-catenin signaling pathway in a cell sample or subject. More specifically, several aspects of the invention provide a set of genes which can be used as biomarkers and gene signatures for evaluating Wnt/.beta.-catenin pathway deregulation status in a sample; classifying a cell sample as having a deregulated or regulated Wnt/.beta.-catenin signaling pathway; determining whether an agent modulates the Wnt/.beta.-catenin signaling pathway in sample; predicting response of a subject to an agent that modulates the Wnt/.beta.-catenin signaling pathway; assigning treatment to a subject; and evaluating the pharmacodynamic effects of therapies designed to regulate Wnt/.beta.-catenin pathway signaling.