Joint damage occurs when structures protecting the joint fail. Because osteoarthritis consists of end-stage joint damage, I propose that risk factors for disease can be best understood as either impairments of joint protectors, increasing joint vulnerability, or as factors that excessively load the joint, leading to injury. I review current knowledge using this paradigm, separating factors into those increasing joint vulnerability (malalignment, muscle weakness, genetic and ethnic predispositions, aging) and those that cause excessive loading (obesity; certain physical activities). Osteoarthritis and cartilage loss can occur without pain. This review focuses separately on factors associated with pain in those with osteoarthritis. To identify sources of pain in osteoarthritis, recent studies have compared magnetic resonance imaging findings of people with osteoarthritis with and without pain, focusing on structures known to have nociceptive innervations. Those with pain are more likely to have effusions, bone marrow lesions, synovial hypertrophy, and tendinitis and bursitis around the joint. This review creates a new paradigm for understanding risk factors for osteoarthritis, using joint vulnerability and loading as a framework and focuses separately on the emerging investigative area of sources of pain.