Aptamer-based smart targeting and spatial trigger–response drug-delivery systems for anticancer therapy have emerged as promising strategies in drug delivery. This review explores the integration of aptamers and stimuli-responsive platforms for enhanced spatial anticancer therapy. Aptamers, short nucleic acid sequences with high specificity and affinity for target molecules, are valuable targeting ligands. They are non-immunogenic, stable, and can be conjugated with drugs or nanocarriers for targeted delivery. Stimuli-responsive systems, such as those responsive to the tumor microenvironment (TME) or external stimuli like ultrasound, light, or magnetic fields, enable controlled drug release. These systems exploit dynamic conditions in cancerous tissues for precise drug delivery. Aptamer-conjugated nanomaterials, including gold, silica, and carbon-based materials, enhance drug delivery efficiency and therapeutic outcomes. For example, aptamer–gold conjugates improve photothermal therapy, while aptamer–silica systems enhance drug loading and targeted delivery. Aptamer–carbon conjugates offer versatile delivery platforms for anticancer agents. Aptamer–drug conjugates, such as those targeting specific cancer markers, show promise in targeted therapy. Stimuli-responsive systems, including those responsive to pH, temperature, or ROS, enable controlled drug release in the TME. These systems enhance therapeutic efficacy while minimizing side effects. The review highlights the potential of aptamers and stimuli-responsive systems in revolutionizing anticancer therapy through precise and targeted drug delivery.Aptamer-based smart targeting and spatial trigger–response drug-delivery systems for anticancer therapy have emerged as promising strategies in drug delivery. This review explores the integration of aptamers and stimuli-responsive platforms for enhanced spatial anticancer therapy. Aptamers, short nucleic acid sequences with high specificity and affinity for target molecules, are valuable targeting ligands. They are non-immunogenic, stable, and can be conjugated with drugs or nanocarriers for targeted delivery. Stimuli-responsive systems, such as those responsive to the tumor microenvironment (TME) or external stimuli like ultrasound, light, or magnetic fields, enable controlled drug release. These systems exploit dynamic conditions in cancerous tissues for precise drug delivery. Aptamer-conjugated nanomaterials, including gold, silica, and carbon-based materials, enhance drug delivery efficiency and therapeutic outcomes. For example, aptamer–gold conjugates improve photothermal therapy, while aptamer–silica systems enhance drug loading and targeted delivery. Aptamer–carbon conjugates offer versatile delivery platforms for anticancer agents. Aptamer–drug conjugates, such as those targeting specific cancer markers, show promise in targeted therapy. Stimuli-responsive systems, including those responsive to pH, temperature, or ROS, enable controlled drug release in the TME. These systems enhance therapeutic efficacy while minimizing side effects. The review highlights the potential of aptamers and stimuli-responsive systems in revolutionizing anticancer therapy through precise and targeted drug delivery.