Here we review the significance of changes in vascular thermotolerance on tumour physiology and the effects of multiple clinically relevant mild temperature hyperthermia (MTH) treatments on tumour oxygenation and corresponding radiation response. Thus far vascular thermotolerance referred to the observation of significantly greater blood flow response by the tumour to a second hyperthermia exposure than in response to a single thermal dose, even at temperatures that would normally cause vascular damage. New information suggests that although hyperthermia is a powerful modifier of tumour blood flow and oxygenation, sequencing and frequency are central parameters in the success of MTH enhancement of radiation therapy. We hypothesise that heat treatments every 2 to 3 days combined with traditional or accelerated radiation fractionation may be maximally effective in exploiting the improved perfusion and oxygenation induced by typical thermal doses given in the clinic.