Environment-mediated drug resistance is a form of de novo drug resistance that protects tumour cells from the initial effects of diverse therapies. Surviving foci of residual disease can then develop complex and permanent acquired resistance in response to the selective pressure of therapy. Recent evidence indicates that environment-mediated drug resistance arises from an adaptive, reciprocal signalling dialogue between tumour cells and the surrounding microenvironment. We propose that new therapeutic strategies targeting this interaction should be applied during initial treatment to prevent the emergence of acquired resistance.