This chapter is as much about the process of reverse engineering as it is about a particular drug delivery system. It presents the materials science and materials engineering concepts that went into the design and testing of the LTSL including: the roles of each of the components that make up the composite membrane; how the molecular and nanostructures that they form might influence the already anomalous permeability at the phase transition of the bilayer; and how this thermally sensitive drug delivery system leads to ultrafast, heat-mediated, triggered, intravascular release of pre-loaded doxorubicin. Release of drug penetrating deep into the tumor interstitium, is controlled by where, when, and for how long mild hyperthermia (HT) is applied 1 in relation to the liposome administration. This formulation, as ThermoDox (R), has been used in a completed 700 patient Phase III human clinical trial in liver cancer (HEAT study), is in a Phase II trial in chest wall recurrence of cancer (DIGNITY study), and is also in a Phase I trial of patients with colorectal liver metastases (ABLATE study). 2 It is a bench-to-bedside story that addresses both overcoming limitations in nanoparticle drug delivery and also the importance of research implementation in translation to the clinic. With additional research and preclinical studies underway, including exploring the use of high frequency ultrasound (HiFu) as a heating modality, and a range of other drugs, imaging agents and biological modifiers poised for encapsulation, the LTSL could provide a new paradigm for drug and agent delivery for the treatment of localized tumors - 'rapid triggered drug release in the tumor bloodstream and deep penetration of drug into the tumor tissue'. Unfortunately, the Phase III trial in liver cancer failed to meet its required endpoints for progression-free survival (PFS). While data is still being analyzed, preclinical and now clinical research shows that it is essential for all future trials of this particular formulation, that the whole tumor should be heated to the desired temperature (41-42 degrees C), and maintained at that temperature while ThermoDox (R) is infused for a minimum of 20 min, and probably an hour, i.e., heat first and then infuse drug.