Nuclear cardiology offers a diverse range of imaging tools that provide valuable insights into myocardial perfusion, inflammation, metabolism, neuroregulation, thrombosis, and microcalcification. These techniques are crucial not only for diagnosing and managing cardiovascular conditions but also for gaining pathophysiologic insights. Surrogate biomarkers in nuclear cardiology, represented by detectable imaging changes, correlate with disease processes or therapeutic responses and can serve as endpoints in clinical trials when they demonstrate a clear link with these processes. By providing early indicators of therapeutic efficacy-often before clinical outcomes manifest-surrogate biomarkers can accelerate treatment development. This disease-focused review will highlight key nuclear cardiology surrogate biomarkers, emphasizing the importance of standardized imaging protocols and robust quantitative techniques to ensure accuracy and reproducibility. We will also explore the challenges to the broader adoption of imaging biomarkers, including the need for well-defined pathophysiologic correlations, greater data diversity in clinical research, and overcoming regulatory barriers. Addressing these challenges will improve the utility of imaging biomarkers in clinical trials, enabling more precise cardiovascular care through early diagnosis and therapeutic monitoring, ultimately accelerating the development of novel cardiovascular therapies.