There is now a growing scientific consensus that the origins of many adult diseases may be attributed to exposure to adversity early in life. Research over the past several decades indicates that many of the most common forms of non-communicable conditions, including both physical and psychiatric disorders, share a common biological foundation involving disruptions to shared biological systems that are likely fundamentally shaped by exposure to early adversity. Despite the enormous promise of existing work, opportunities for clinical translation remain limited. Thus, we argue that it is now crucial to pause and consider the directions in which the field needs to move to ensure continued progress with the aim of protecting at-risk youth against the development of life-long disease. We first review recent work that has meaningfully contributed to a developmental cascade model wherein early life adversity sets off a cascade of dysregulations in the neuroendocrine, immune, and metabolic systems, which bidirectionally influence and are influenced by neural and epigenetic factors. We then outline four key directions for future work that we contend must be emphasized to maximize the clinical impact of this maturing field, including cross-disciplinary collaborations, multi-biomarker approaches, modeling disease processes prior to illness onset, and nuanced characterization of the early environment. Recent work highlights nuanced pathways through which early life adversity contributes to the development of a biological foundation underlying risk for non-communicable conditions. We contend that it is crucial to reflect on future research directions to ensure continued progress and opportunities for clinical translation, as the development of an increasingly sophisticated understanding of the pathways linking adversity to illness holds enormous promise for our ability to promote health and prevent disease among at-risk youth.