New developments are presented in the design of stimuli-responsive liposomes for targeted delivery via the construction of a liposome membrane (lipid bilayer) using amphiphiles able to perform a stimuli-triggered conformational flip (“flipids”). When done simultaneously by a major or significant part of the bilayer molecules, this massive flip disrupts the liposome membrane and induces a rapid release of the liposome load specifically in response to the initial stimulus. The conformational switches incorporated into the amphiphilic molecules could potentially be controlled by various internal or external factors (pH, metal complexation, light, etc.). Using this concept we designed a series of pH-triggerable “flipids”, and prepared and tested “fliposomes” with extraordinary characteristics: high stability in storage and in serum combined with an instant release of their cargo in response to a weakly acidic medium.