Progressive knee joint degeneration occurs following removal of a torn meniscus. However, there is significant variability in the rate of development of post-meniscectomy osteoarthritis (OA). While there is no current consensus on the risk factors for development of knee OA in patients with meniscus tears, it is likely that both biological and biomechanical factors play critical roles. In this perspective paper, we review the mechanical and the biological predictors of the response of the knee to partial meniscectomy. We review the role of patient-based studies, in vivo animal models, cadaveric models, bioreactor systems, and statistically augmented computational models for the study of meniscus function and post-meniscectomy OA, providing insight into the important interplay between biomechanical and biologic factors. We then discuss the clinical translation of these concepts for "biologic augmentation" of meniscus healing and meniscus replacement. Ultimately, collaborative studies between engineers, biologists, and clinicians is the optimal way to improve our understanding of meniscus pathology and response to injury and/or disease, and to facilitate effective translation of laboratory findings to improved treatments for our patients.