Sickness is a normal response to infections or stress triggered by proinflammatory cytokines that drive local and systemic inflammatory responses. Proinflammatory cytokines act on the brain causing the so called “sickness behavior,”which is thought to improve recovery but can become maladaptive in the long term. Chronic inflammation characterizes many diseases and there is some evidence that dogs and cats experience age-associated increases in inflammation, a condition named “inflammaging.” A complex and multifactorial relationship exists between these inflammatory mechanisms, pain, and psychological illness that may complicate veterinary diagnosis and affect the outcome.