A hallmark of many diseases, such as cancer, neurological conditions, and metabolic syndromes, is dysfunctional cellular bioenergetics. Often, conventional in vitro models are not able to accurately replicate the complex cellular and metabolic interactions that are seen in vivo. One promising way to overcome this is through the development of higher order in vitro models, such as organoids, 3D cell cultures, and organs-on-chips. The study of intricate mitochondrial bioenergetic mechanisms and their dysregulation in disease situations is made possible by these sophisticated models, which offer a microenvironment that is more physiologically appropriate. This chapter explores the use of higher order in vitro models to analyse the mechanisms of dysregulated bioenergetics and in drug development. It explores how these models provide a more accurate description of disease states by capturing the dynamic interplay between cells, the extracellular matrix, and microenvironmental variables. Furthermore, the incorporation of these models into drug development pipelines may improve the predictive power of preclinical research, enabling the discovery of new therapeutic targets and a more accurate assessment of drug candidates. Targeted therapy development is accelerated, and disease pathophysiology is better understood by the synergistic combination of patient-derived higher-order in vitro models and dysregulated bioenergetics research.