Purpose Thinning of cartilage is a common manifestation of osteoarthritis. This study addresses the need of measuring the focal femoral cartilage thickness at the weight-bearing regions of the knee by developing a reproducible and automatic method from MR images. Methods 3D models derived from semiautomatic MR image segmentations were used in this study. Two different methods were examined for identifying the mechanical loading of the knee articulation. The first was based on a generic weight-bearing regions definition, derived from gait characteristics and cadaver studies. The second used a physically based simulation to identify the patient-specific stress distribution of the femoral cartilage, taking into account the forces and movements of the knee. For this purpose, four different scenarios were defined in our 3D finite element (FE) simulations. The radial method was used to calculate the cartilage thickness in stress-based regions of interest, and a study was performed to validate the accuracy and suitability of the radial thickness measurements. Results Detailed focal maps using our simulation data and regional measurements of cartilage thickness are given. We present the outcome of the different simulation scenarios and discuss how the internal/external rotations of the knee alter the overall stress distribution and affect the shape and size of the calculated weight-bearing areas. The use of FE simulations allows for a patient-specific calculation of the focal cartilage thickness. Conclusion It is important to assess the quantification of focal knee cartilage morphology to monitor the progression of joint diseases or related treatments. When this assessment is based on MR images, accurate and robust tools are required. In this paper, we presented a set of techniques and methodologies in order to accomplish this goal and move toward personalized medicine.