Dysregulation of Wnt signaling is common in a variety of human malignancies. Activation of the canonical Wnt or beta-catenin pathway has been especially well documented in cancer, although other non-canonical Wnt signaling pathways also have been implicated in neoplasia. In most instances, constitutive signaling through the beta-catenin pathway involves activation of effector molecules or loss of tumor suppressor function downstream of Wnt binding to its cell surface receptors. Nonetheless, in recent years increasing evidence suggests that secreted Wnt antagonists act as tumor suppressors, with their expression often silenced by promoter hypermethylation. This implies that maximal constitutive signaling in cancer requires unimpaired Wnt stimulation at the cell surface as well as enhanced signal propagation within the cell. However, an understanding of the role secreted Wnt antagonists may play in cancer is complicated by the multiplicity of these proteins, their potential Wnt-independent activities and observations indicating that sometimes they may promote tumor growth. Just as the particular function of Wnt signaling in development and homeostasis varies with the setting, the impact of secreted Wnt antagonists on neoplasia depends on the molecular, cellular and tissue context.