In addition to biological cues, the cellular microenvironment is rife with physical cues that coordinate cellular behavior through regulation of signaling pathways such as the transforming growth factor beta (TGFβ) pathway. These cues – substrate stiffness or topography, mechanical compression, tension, or fluid shear stress, among others – exert their effects in controlling major cellular decisions such as proliferation, migration, or differentiation through direct and indirect processes. In the skeleton, accurate cellular detection of physical changes in the microenvironment is necessary to preserve homeostasis, and disruption of this can drive disease progression. For example, in bone, mechanoregulation of the TGFβ pathway in response to mechanical compression is required for bone anabolism. Likewise, in cartilage, dysregulation of TGFβ signaling can promote an osteoarthritic phenotype. However, the set of mechanisms that enable mechanoregulation of TGFβ signaling remain to be fully elucidated. This work uses molecular biology, engineering, and computational approaches to investigate the molecular mechanisms underlying regulation of the TGFβ signaling pathway by substrate stiffness/cytoskeletal tension and fluid shear stress, two major physical cues within the context of the skeleton. These findings reveal new roles for TGFβ receptors in defining the cellular TGFβ response to changes in physical cues in the microenvironment.