Reliability of materials refers to how well an engineered material performs its intended function over a targeted design lifetime. Quantitatively, reliability is defined as (1 − probability of failure). Because a material’s physical properties are determined by its atomic makeup, reliable material function fundamentally depends on the stability of atomic structure as that material sees continued exposure to operational conditions. From the interconnect perspective, the primary functions include routing signal and power within and between devices or other subcomponents. Any disruptions to the atomic arrangement of materials used as interconnects therefore change the ability of those interconnects to perform those functions. An important aspect of designing these structures for high reliability therefore involves measuring and understanding how operational stressors can lead to the formation and evolution of defects in atomic structure over time. This type of knowledge can then at a minimum be used to predict when those effects unacceptably compromise interconnect functionality. Better yet, it can be used to improve material processing to slow or even eliminate damage. While interconnect technology has undergone significant changes and improvements over the years due to new materials, material systems, dimensions, and architectures, the fundamental factors that remain a chronic concern for reliability of interconnects used in BEOL and packaging are a combination of temperature, electric current, and mechanical strain. Our work addresses methods to test, detect, and ultimately control material defects, reliability, and failure. In this contribution, I will summarize some of our work to measure damage due to thermal fatigue and electromigration in several materials, including aluminum, copper, carbon nanotubes, and 2D molybdenum disulfide. I will also summarize some of our recent developments in material characterization, which we believe can play an important role in assessing material reliability for the semiconductor industry.