Cellular membranes are dynamic chemical systems whose structural and functional properties are governed by complex lipid compositions and macromolecular interactions. Recent advances in lipidomics have reshaped our understanding of membrane biology, revealing that lipid diversity, spatial organization, and chemical modifications play central roles in regulating cellular processes. In chronic diseases, including metabolic disorders, cardiovascular pathology, neurodegeneration, and cancer, membrane lipid homeostasis is profoundly disrupted. These alterations involve shifts in phospholipid saturation, cholesterol distribution, sphingolipid metabolism, and oxidative lipid damage, leading to significant changes in membrane fluidity, permeability, and signaling efficiency. Such biophysical perturbations contribute to impaired receptor function, mitochondrial dysfunction, inflammatory activation, and dysregulated cell death pathways. This review synthesizes current knowledge on lipidomic remodeling of cellular membranes and highlights how chemical alterations translate into downstream biophysical and cellular consequences. Furthermore, it emphasizes the role of lipidomics as a powerful analytical framework for identifying disease-associated membrane signatures and exploring potential diagnostic and therapeutic applications. Overall, membrane lipid remodeling emerges not as a secondary epiphenomenon but as a central mechanistic feature in the pathophysiology of chronic diseases.