In this issue of PET Clinics, guest editors Drs. Nicolas A. Karakatsanis and Abass Alavi bring their considerable expertise to the topic of PET Image Quantification:: Novel Methods, Challenges, and Opportunities. Top experts present an overview of the latest developments and challenges in quantitative clinical PET data correction methods and how the latest advancements in multi-parametric imaging, dual-tracer protocols, artificial intelligence, and total-body scanners are paving the way to overcome current challenges and open new opportunities for improved quantitative accuracy.