Small molecule high throughput screening (HTS) in drug discovery traditionally involves microtiter plate screening in 384- and 1536- well formats. While these methods are miniaturized compared to petri dishes or flasks, reagent and labor costs are still significant factors in high throughput screening campaigns. Here we present the development of cellular assays utilizing ultraminiaturized array-based and microfluidic devices. The experiments were aimed at reducing cellular assay volumes from uL to nL volumes. Challenges included maintaining environmental controls for cell health and handling small volumes for cells and compounds. Novel approaches in equipment, device design, and automation were required. Data suggest that cell health, cell morphology, and pharmcological responses to drugs were similar in nL volumes compared to those observed in 50 uL volumes in 384 well plates. Development of processes and automation to industrialize new devices will ultimately enable these technologies to be applied broadly in drug discovery. Cost savings in cell and reagent usage, and the ability to use disease relevant cell systems are paths toward reduced attrition in drug discovery.