This paper describes how we have used material science, physical chemistry, and some luck, to design a new thermal-sensitive liposome (the low temperature sensitive liposome (LTSL)) that responds at clinically attainable hyperthermic temperatures releasing its drug in a matter of seconds as it passes through the microvasculature of a warmed tumor. The LTSL is composed of a judicial combination of three component lipids, each with a specific function and each affecting specific material properties, including a sharp thermal transition and a rapid on-set of membrane permeability to small ions, drugs and small dextran polymers. Experimentally, the paper describes how bilayer-concentration changes involving the lysolipid and the presence or absence of DSPE–PEG2000 affect both the lipid transition temperature and the drug release. While the inclusion of 4 mol% DSPE–PEG2000 raises the transition temperature peak (Tm) by about 1 °C, the inclusion of 5.0, 9.7, 12.7 and 18.0 mol% MSPC slightly lowered this peak back to 41.7 °C, while not further broadening the peak breadth. As for drug release, in the absence of MSPC, the encapsulated doxorubicin-citrate is hardly released at all. Increasing the composition of MSPC in the lipid mixture (5.0, 7.4, 8.5 and 9.3 mol% MSPC) shows faster and faster initial doxorubicin release rates, with 8.5 and 9.3 mol% MSPC formulations giving 80% of encapsulated drug released in 4 and 3 min, respectively. The Thermodox® formulation (9.7 mol% MSPC) gives 60% released in the first 20 s. The presence of PEG–lipid is found to be essential in order for the lysolipid-induced permeability to reach these very fast times. From drug and dextran release experiments, and estimates of the molecular and pore size, the conclusions are that: in order to induce lasting nanopores in lipid bilayers ∼10 nm diameter, they initially require the presence (from the solid phase structure) of grain boundary defects at the DPPC transition and the permeabilizing component(s) can either be a pore forming lysolipid/surfactant plus a PEG–lipid, or can be generated by a PEG–surfactant incorporated at ∼4–5 mol%. The final discussion is centered around the postulated defect structures that result in membrane leakage and the permeability of doxorubicin and H+ ions.