The term osteoarthritis (OA) represents a group of diseases characterized by gradual degradation of articular cartilage and a number of associated degenerative processes within the joint. Consequently, no single animal model is likely to fulfil all the criteria of OA. The present chapter discusses the possibilities of using transgenic technologies for modification of the mouse genome to generate animal models of OA. After discussing the different approaches available, we provide an example of the generation of a traditional transgenic mouse strain and describe techniques and practical aspects of genotyping as well as the preparation of skeletal samples for radiological, histological, immunohistological, and molecular biologic analyses for phenotype characterization. We also present a histological grading system to evaluate the progression of OA lesions, with examples of other degenerative alterations in the knee joint structures.