As infrastructure systems evolve into intelligent, interconnected cyber–physical systems (CPSs), traditional reliability-centered approaches are proving insufficient. This article introduces dependability-centered asset management (DCAM)—a forward-looking, system-level framework that unifies engineering, computing, and sustainability to manage assets in the CPS era. DCAM addresses the limitations of fragmented reliability and dependability practices by integrating lifecycle awareness, artificial intelligence (AI) and digital twins, adaptive decision-making, and distributed intelligence infrastructure. It emphasizes not only the use of AI to enhance asset reliability but also the importance of managing AI itself as a dependable asset. Real-world applications across energy, transportation, healthcare, and public infrastructure illustrate DCAM’s potential to deliver resilient, trustworthy, and sustainable systems. This article concludes with future directions, including the role of emerging technologies such as blockchain and extended reality (XR), the need for new metrics, and the importance of interdisciplinary education and standards.