Cell migration is an adaptive process that depends on and responds to physical and molecular triggers. Moving cells sense and respond to tissue mechanics and induce transient or permanent tissue modifications, including extracellular matrix stiffening, compression and deformation, protein unfolding, proteolytic remodeling and jamming transitions. Friedl and his team have developed high-resolution technology to follow the behavior of migrating tumor cells in tissues. This knowledge contributes to better understanding how the bi-directional relationship of cell–tissue interactions (mechano-reciprocity) allows cells to change position and contributes to single-cell and collective movement, structural and molecular tissue organization, and cell fate decisions. The enclosed illustration by Weigelin and Friedl shows melanoma cells with dark blue nuclei use muscle fibers, nerve fibers and blood vessels to find their way as they infiltrate mouse skin tissue (Proc Natl Acad Sci USA 2015).