Osteoarthritis and cancer are the inevitable consequences of aging and significantly contribute to the cause of death in cats and dogs. Managing the pain associated with these disease states is the veterinarian’s mandate. Many treatment modalities and agents are available for patient management; however, it is only with an understanding of disease neurobiology and a mechanism-based approach to problem diagnosis that the clinician can offer patients an optimal quality of life based on evidence-based best medicine. When treating pain, knowledge is still our best weapon.