Molecular medicine is founded on the synergy between Chemistry, Physics, Biology and Medicine, with the ambitious goal of tackling diseases from a molecular perspective. This Review aims at retracing a personal outlook of the birth and development of molecular medicine, as well as at highlighting some of the most urgent challenges linked to aging and represented by incurable neurodegenerative diseases caused by protein misfolding. Furthermore, we emphasize the emerging role of the retromer dysfunctions and improper protein sorting in Alzheimer's disease and other important neurological disordered.