A new electro-thermally induced structural failure actuator (ETISFA) is introduced as an activation mechanism for on demand controlled drug delivery from a Micro-Electro-Mechanical-System (MEMS). The device architecture is based on a reservoir that is sealed by a silicon nitride membrane. The release mechanism consists of an electrical fuse constructed on the membrane. Activation causes thermal shock of the suspended membrane allowing the drugs inside of the reservoir to diffuse out into the region of interest. The effects of fuse width and thickness were explored by observing the extent to which the membrane was ruptured and the required energy input. Device design and optimization simulations of the opening mechanism are presented, as well as experimental data showing optimal energy consumption per fuse geometry. In vitro release experiments demonstrated repeatable release curves of mannitol-C14 that precisely follow ideal first order release kinetics. Thermally induced structural failure was demonstrated as a feasible activation mechanism that holds great promise for controlled release in biomedical microdevices.