Detecting light, photon by photon, has been possible since the 1930s, with the invention of the photomultiplier tube (PMT). However, it is only since the 1970s, that solid-state single-photon detectors have emerged and only since 2003 that a new technology, known as single-photon avalanche diode (SPAD) has become CMOS-compatible. The SPAD technology is scalable, low-cost, and it is natively digital, thereby enabling a variety of sensor architectures optimized for applications, such as bioimaging, high energy physics, and medical physics. Thanks to the adaptability of SPADs to many different CMOS technologies, it is possible to achieve systems of different complexity, operating conditions, and, ultimately, cost. The versatility of this device, makes it ideal in very different applications, where it is emerging as the sensor of choice. This thesis focuses on improving CMOS SPAD performance for time-of-flight PET, while other applications, such as FLIM and LiDAR could also benefit from the technology developed here. We have designed SPAD-based sensors in two different silicon standard technology nodes and we have fully analyzed their performance. We have also explored the optimization of light extraction in inorganic scintillator-based detector modules and direct particle detection and we have studied two applications beyond PET. The thesis is organized as follows. After a comprehensive description of SPAD technology, we focus on new SPADs structures in standard deep-submicron technology nodes, 180 nm CMOS and 55 nm BCD. The results achieved with these devices show how SPADs can achieve an unprecedented timing performance of 7.5 ps FWHM at room temperature with a sensitivity peak of 55% thanks to a fully integrated front-end readout system that is shown to play an essential role here. We show that state-of-the-art performance is possible using advanced standard technology nodes, where outstanding timing and sensitivity performance were achieved by systematically engineering the electric field in multiplication and drift regions to achieve optimized carrier generation and transport upon detection. We have demonstrated the first large-scale 3D-stacked frontside-illuminated (FSI) multi-digital silicon photomultiplier (MD-SiPM), whereas we discuss the sensor structure and its electronic components aimed at modularity and scalability, so as to ultimately achieve large-format SPAD sensors. To demonstrate specific aspects of the intended applications, in primis, TOF-PET, we look at coupling between photodetectors and inorganic scintillators, where gamma radiations, originated from electron-positron annihilations, are detected. Using photonic crystals structures, nanoimprinted on the scintillator output surface, we have demonstrated a 40% improvement in light extraction and 25% better energy resolution in BGO crystals. Finally, we explore the use of SPADs for direct time-of-flight coincidence measurements of minimum ionizing particles. We achieved an unprecedented 9.4 ps coincidence uncertainty in this novel and very thought-provoking SPAD application, corresponding to a 6 ps Gaussian sigma timing resolution for a single detector. In summary, this thesis demonstrates new paradigms of SPAD performance, together with a novel 3D integration of FSI SPADs, and novel application solutions. In the future, we thus expect that these achievements will pave the way for further performance improvements and extensive scientific explorations.