Advances in materials engineering have allowed for the development of sophisticated and controlled drug delivery through vesicles. Smart vesicles, capable of sensing single stimulus or multiple stimuli, can be engineered to process specific environmental signals to produce a tailored response. Exhibiting multifunctionality and theranostic abilities, they are a promising platform for new therapeutic methods. Here, we discuss smartness in the context of biosensing vesicles, followed by the various components required to develop a smart vesicle and the design considerations regarding engineering approaches of each. We then focus on biomedical applications of the vesicles in disease treatment and biosensing.