Though the existence of cancer stem cells remained enigmatic initially, over the time their participation in tumorigenesis and tumor progression has become highly evident. Today, they are also appreciated as the causal element for tumor heterogeneity and drug-resistance. Cancer stem cells activate a set of molecular pathways some of which are triggered by the unique mechanical properties of the tumor tissue stroma. A relatively new field called mechanobiology has emerged, which aims to critically evaluate the mechanical properties associated with biological events like tissue morphogenesis, cell-cell or cell-matrix interactions, cellular migration and also the development and progression of cancer. Development of more realistic model systems and biophysical instrumentation for observation and manipulation of cell-dynamics in real-time has invoked a hope for some novel therapeutic modalities against cancer in the future. This review discusses the fundamental concepts of cancer stem cells from an intriguing viewpoint of mechanobiology and some important breakthroughs to date.