The cancer stem cell (CSC) concept, which arose about a decade ago, proposes that tumor growth is sustained by a subpopulation of highly malignant cells. These cells, termed CSCs, are capable of extensive self-renewal that contributes to metastasis and treatment resistance. Therefore, therapeutic strategies that target CSCs should be developed for improving outcomes of cancer patients. Recent progress has highlighted the importance of physical properties of the extracellular matrix and mechanotransduction pathway in cancer cells during cancer development. On the other hand, the significance of CXCR1, an upstream signal of FAK/PI3K/Akt has been revealed in CSCs. FAK/PI3K/Akt is a key signal mediator in mechanotransduction pathway. Therefore, mechanotransduction could be a new target for CSCs, and would be an innovative way to treat cancer by inhibiting FAK/PI3K/Akt.