INTRODUCTION: Nanocarrier-based delivery systems offer multiple benefits to overcome limitations of the traditional drug dosage forms, such as protection of the drug, enhanced bioavailability, targeted delivery to disease site, etc. Nanocarriers have exhibited tremendous successes in targeted delivery of therapeutics to the desired tissues and cells with improved bioavailability, high drug loading capacity, enhanced intracellular delivery, and better therapeutic effect. A specific design of stimuli-responsive nanocarriers allows for changing their structural and physicochemical properties in response to exogenous and endogenous stimuli. These nanocarriers show a promise in site specific controlled release of therapeutics under certain physiological conditions or external stimuli. AREAS COVERED: This review highlights recent progresses on the multifunctional and stimuli-sensitive nanocarriers for targeted therapeutic drug delivery applications. EXPERT OPINION: The progress from single functional to multifunctional nanocarriers has shown tremendous potential for targeted delivery of therapeutics. On our opinion, the future of targeted delivery of drugs, nucleic acids, and other substances belongs to the site-targeted multifunctional and stimuli-based nanoparticles with controlled release. Targeting of nanocarriers to the disease site enhance the efficacy of the treatment by delivering more therapeutics specifically to the affected cells and substantially limiting adverse side effects upon healthy organs, tissues, and cells.