Aptamers, synthetic nucleic acid molecules with high specificity and tunable binding properties, are emerging as promising tools for neurochemical biosensing. This Perspective discusses the potential of aptamers in overcoming challenges in neurochemical biosensing, such as nonspecific binding and the need for high selectivity. The article highlights the importance of characterizing aptamer thermodynamics and target binding to develop functional biosensors in biological systems. Two label-free affinity platforms, field-effect transistors and nanopores, are discussed, with a focus on structure-switching aptamers that can overcome the Debye length limitation and enhance signal transduction. The integration of aptamers into these platforms enables sensitive, real-time, and localized measurements with potential for clinical translation. The article also addresses challenges in aptasensing, including biofouling, nuclease degradation, and the need for high sensitivity and selectivity in complex biological environments. The development of aptamer-based biosensors requires careful consideration of aptamer design, characterization, and integration into biosensing platforms. The article emphasizes the importance of multidisciplinary approaches in advancing aptamer-based biosensors for neuroscience and human health. The potential of aptamers in neurochemical sensing is highlighted, with applications in monitoring neurotransmitters such as dopamine, which is crucial for understanding brain function and disease. The integration of aptamers with electronic and optical sensors offers a promising avenue for advancing neurochemical sensing technologies. The article concludes with a vision of aptamers as both diagnostic and therapeutic agents, capable of enabling precise monitoring of small-molecule biomarkers in biofluids and facilitating personalized medicine. The development of aptamer-based biosensors requires continued research and innovation to address remaining challenges and expand their applications in neuroscience and human health.Aptamers, synthetic nucleic acid molecules with high specificity and tunable binding properties, are emerging as promising tools for neurochemical biosensing. This Perspective discusses the potential of aptamers in overcoming challenges in neurochemical biosensing, such as nonspecific binding and the need for high selectivity. The article highlights the importance of characterizing aptamer thermodynamics and target binding to develop functional biosensors in biological systems. Two label-free affinity platforms, field-effect transistors and nanopores, are discussed, with a focus on structure-switching aptamers that can overcome the Debye length limitation and enhance signal transduction. The integration of aptamers into these platforms enables sensitive, real-time, and localized measurements with potential for clinical translation. The article also addresses challenges in aptasensing, including biofouling, nuclease degradation, and the need for high sensitivity and selectivity in complex biological environments. The development of aptamer-based biosensors requires careful consideration of aptamer design, characterization, and integration into biosensing platforms. The article emphasizes the importance of multidisciplinary approaches in advancing aptamer-based biosensors for neuroscience and human health. The potential of aptamers in neurochemical sensing is highlighted, with applications in monitoring neurotransmitters such as dopamine, which is crucial for understanding brain function and disease. The integration of aptamers with electronic and optical sensors offers a promising avenue for advancing neurochemical sensing technologies. The article concludes with a vision of aptamers as both diagnostic and therapeutic agents, capable of enabling precise monitoring of small-molecule biomarkers in biofluids and facilitating personalized medicine. The development of aptamer-based biosensors requires continued research and innovation to address remaining challenges and expand their applications in neuroscience and human health.