The growing understanding of the dynamic role of TG2 as cancer evolves and progresses, coupled to the enormous efforts characterising the mechanical events driving cancer cell survival and invasion, suggest that pre-clinical development focussed on an appropriate window of opportunity has the potential to position TG2 as a valid, useful, biological, and biomechanical target to expand the options available for the treatment of cancers, particularly advanced-stage tumours that show extensive ECM deposition and remodelling, and that currently have poor prognosis. The gene discussed is TGM2; the disease is neoplasm.