Identifying relationships between molecular variations and their clinical presentations has been challenged by the heterogeneous causes of a disease. It is imperative to unveil the relationship between the high dimensional molecular manifestations and the clinical presentations, while taking into account the possible heterogeneity of the study subjects. We proposed a novel supervised clustering algorithm using penalized mixture regression model, called CSMR, to deal with the challenges in studying the heterogeneous relationships between high dimensional molecular features to a phenotype. The algorithm was adapted from the classification expectation maximization algorithm, which offers a novel supervised solution to the clustering problem, with substantial improvement on both the computational efficiency and biological interpretability. Experimental evaluation on simulated benchmark datasets demonstrated that the CSMR can accurately identify the subspaces on which subset of features are explanatory to the response variables, and it outperformed the baseline methods. Application of CSMR on a drug sensitivity dataset again demonstrated the superior performance of CSMR over the others, where CSMR is powerful in recapitulating the distinct subgroups hidden in the pool of cell lines with regards to their coping mechanisms to different drugs. CSMR represents a big data analysis tool with the potential to resolve the complexity of translating the clinical manifestations of the disease to the real causes underpinning it. We believe that it will bring new understanding to the molecular basis of a disease, and could be of special relevance in the growing field of personalized medicine.