High-throughput technologies have become essential in many fields of pharmaceutical and biological development and production. Such technologies were initially developed with compatibility with liquid handling-based cell culture techniques to produce large-scale 2D cell culture experiments for the compound analysis of candidate drug compounds. Over the past two decades, tools for creating 3D cell cultures, organoids, and other 3D in vitro models, such as cell supportive biomaterials and 3D bioprinting, have rapidly advanced. Concurrently, a significant body of evidence has accumulated which speaks to the many benefits that 3D model systems have over traditional 2D cell cultures. Specifically, 3D cellular models better mimic aspects such as diffusion kinetics, cell-cell interactions, cell-matrix interactions, inclusion of stroma, and other features native to in vivo tissue and as such have become an integral part of academic research. However, most high throughput assays were not developed to specifically support 3D systems. Here, we describe the need for improved compatibility and relevant advances toward deployment and adoption of high throughput 3D models to improve disease modeling, drug efficacy testing, and precision medicine applications.