Aptamers bind to their targets with high affinity and specificity through structure-based complementarity, instead of sequence complementarity that is used by most of the oligonucleotide-based therapeutics. This property has been exploited in using aptamers as multifunctional therapeutic units, by attaching them to therapeutic drugs, nanoparticles, or imaging agents, or as direct molecular decoys for inducing loss-of-function or gain-of-function of targets. One of the most interesting fields of aptamer application is their development as molecular sensors to regulate artificial riboswitches. Naturally, the riboswitches sense small-molecule metabolites and respond by regulating the expression of the corresponding metabolic genes. Riboswitches are cis-acting RNA structures that consist of the sensing (aptamer) and the regulating (expression platform) domains. In principle, diverse riboswitches can be engineered and applied to control different steps of gene expression in bacterial species as well as eukaryotes, by simply replacing aptamers against various endogenous and/or exogenous targets. Although these engineered aptamer-based riboswitches are recently gaining attention, it is clear that aptamer-based riboswitches have a potential for next-generation therapeutics against various diseases because of their controllability, specificity, and modularity in regulating gene expression through various cellular processes, including transcription, splicing, stability, RNA interference, and translation. In this review, we provide a summary of the recently developed and engineered aptamer-based riboswitches focusing on their therapeutic availability and further discuss their clinical potential.