Objective. To systematically review the evidence for a relationship between malalignment of the knee joint and progression and/or development of knee osteoarthritis (OA). Methods. Electronic searches of Medline, EMBase, and CINAHL were performed up to July 2008 using medical subject headings and free-text words. We included radiographic or magnetic resonance imaging (MRI) studies that met a set of predefined criteria. Two independent reviewers extracted the data and assessed the methodologic quality of the selected studies. Due to both heterogeneity and a limited number of studies, the results were summarized using a best evidence synthesis. Results. Fourteen studies met our inclusion criteria and 8 were considered high quality. We found limited evidence for an association between knee malalignment and incident knee OA, because only 1 cohort study examined this relationship. However, there was strong evidence based on 4 high-quality cohort studies that knee malalignment is an independent risk factor for progression of radiographic knee OA. This finding was further supported by 2 high-quality MRI cohort studies that found a relationship between varus and valgus alignment and structural progression of knee OA. Conclusion. Malalignment of the knee joint was found to be an independent risk factor for the progression of knee OA. Given the paucity of investigation into the relationship between knee malalignment and risk of incident OA, further high-quality cohort studies are needed, and these may have important implications for the prevention of knee OA.