Metastatic cancer spread to the skeleton is the most common distant site for many cancer types, including breast and prostate, yet it is incurable. Dynamic mechanical signaling, which results from physical activity imparting forces on the skeleton, is inherent to the bone microenvironment and is critical for regulating the bone remodeling balance (bone formation vs. loss). Metastatic cancer cells are exposed to mechanical signals when they localize to the skeleton, yet how their phenotype and function is mechano-regulated is unknown. In particular, how metastatic cancer cells interact with the large mechano-responsive bone cell population is ill-defined. This talk will discuss both experimental and computational approaches for investigating the effects of mechanical loading on bone metastasis as well as work indicating that mechanical loading plays an inhibitory role in bone metastatic progression.