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Chenbo Dong, Xiao Hu, Cerasela Zoica Dinu Department of Chemical and Biomedical Engineering, West Virginia University, Morgantown, WV, USA Abstract: Understanding the complex interplay between cells and their biomechanics and how the interplay is influenced by the extracellular microenvironment, as well as how the transforming potential of a tissue from a benign to a cancerous one is related to the dynamics of both the cell and its surroundings, holds promise for the development of targeted translational therapies. This review provides a comprehensive overview of atomic force microscopy-based technology and its applications for identification of cellular progression to a cancerous phenotype. The review also offers insights into the advancements that are required for the next user-controlled tool to allow for the identification of early cell transformation and thus potentially lead to improved therapeutic outcomes. Keywords: atomic force microscopy (AFM), nanoindentation, malignant transformation, cancerous phenotype, bio-nano-mechanical signature