This Perspective elucidates the transformative impacts of advanced nanotechnology and dynamic energy systems on the polymer chain reaction (PCR), a cornerstone technique in biomedical research and diagnostic applications. Since its invention, the optimization of PCR-specifically its efficiency, specificity, cycling rate, and detection sensitivity-has been a focal point of scientific exploration. Our analysis spans the modulation of PCR from both material and energetic perspectives, emphasizing the intricate interplay between PCR components and externally added entities such as molecules, nanoparticles (NPs), and optical microcavities. We begin with a foundational overview of PCR, detailing the basic principles of PCR modulation through molecular additives to highlight material-level interactions. Then, we delve into how NPs, with their diverse material and surface properties, influence PCR through interface interactions and hydrothermal conduction, drawing parallels to molecular behaviors. Additionally, this Perspective ventures into the energetic regulation of PCR, examining the roles of electromagnetic radiation and optical resonators. We underscore the advanced capabilities of optical technologies in PCR regulation, characterized by their ultrafast, residue-free, and noninvasive nature, alongside label-free detection methods. Notably, optical resonators present a pioneering approach to control PCR processes even in the absence of light, targeting the often-overlooked water component in PCR. By integrating discussions on photocaging and vibrational strong coupling, this review presents innovative methods for the precise regulation of PCR processes, envisioning a new era of PCR technology that enhances both research and clinical diagnostics. The synergy between nanotechnological enhancements and energy dynamics not only enriches our understanding of PCR but also opens new avenues for developing rapid, accurate, and efficient PCR systems. We hope that this Perspective will inspire further innovations in PCR technology and guide the development of next-generation clinical detection instruments.