In the area of drug delivery, novel tools and technological approaches have captured the attention of researchers in order to improve the performance of conventional therapeutics and patient compliance to pharmacological therapy. Stimuli-responsive drug delivery systems (DDS) appear as a promising approach to control and target drug delivery. When these DDS are administered, the drug release is activated and then modulated through some action or external input and facilitated by the energy supplied externally. The stimuli responsible to activate the drug release can be classified into three types according to their nature or the type of energy applied: physical (e.g. magnetic field, electric field, ultrasound, temperature and osmotic pressure); chemical (e.g. pH, ionic strength and glucose); and biological (enzymes and endogenous receptors). The present review gives an overview of the most significant physical and chemical stimuliresponsive DDS and elucidates about their current and relevant applications in controlled and targeted drug delivery attending different routes of administration.