In this Review, we attempt to offer a thorough description of all of the chemical components and the rationale behind the design of temperature-sensitive vesicle systems, as well as the critical pharmacological parameters that need to be combined to achieve their successful clinical translation. The focus of this Review will be predominantly on the design principles around the construction of temperature-sensitive liposomes (TSL) and their use in combination with external local hyperthermia to achieve heat-triggered drug release. The emphasis lies on the chemical components synthesized and incorporated in the design and engineering of TSL. We conclude that the development of TSL with ultrafast drug release capabilities needs to progress in parallel with vesicle pharmacokinetic profiling, imaging, and monitoring capacity and technologies for accurate temperature elevation and control. The development of heat-triggered liposome systems offer the greatest opportunity for clinical translation of the next generation, nanoscale “smart” vesicle systems of enhanced functionality, following from the successful legacy and rich clinical history from multiple earlier liposome technologies.