With the rapid development of electronic information technology in the 5G era towards high integration, short propagation delay, and elevated assembly temperatures, more academic and industrial attention has been focused on high-frequency and high-speed copper-clad laminates (CCLs). Compared with conventional polymeric matrices, thermoset polyphenylene oxide (PPO) has become one of the most attractive resins applied in high-performance CCLs (HPCCLs) because of its excellent comprehensive properties, including outstanding dielectric properties, high thermal stability, great processibility, and low moisture absorption, etc. This review focuses on the history of the development of PPO prepolymers/oligomers, PPO-based thermoset resin systems, and PPO/inorganic filler composites to optimize the dielectric constant, dielectric loss, thermal conductivity, coefficient of thermal expansion, and mechanical properties. Moreover, some current challenges of PPO-based thermoset systems have been identified, such as developing feasible solutions to ensure the anti-aging properties for long-term reliability under harsh environments of high temperature, high humidity, and even high-frequency electromagnetic radiation. In general, more in-depth investigations of PPO-based thermoset systems for HPCCLs are required in the future.