Wnt signaling pathways constitute a group of signal transduction pathways that direct many physiological processes, such as development, growth, and differentiation. Dysregulation of these pathways is thus associated with many pathological processes, including neurodegenerative diseases, metabolic disorders, and cancer. At the same time, alterations are observed in plasma membrane compositions, lipid organizations, and ordered membrane domains in brain and metabolic diseases that are associated with Wnt signaling pathway activation. Here, we discuss the relationships between plasma membrane components-specifically ligands, (co) receptors, and extracellular or membrane-associated modulators-to activate Wnt pathways in several brain and metabolic diseases. Thus, the Wnt-receptor complex can be targeted based on the composition and organization of the plasma membrane, in order to develop effective targeted therapy drugs.