The National Institutes of Health Microphysiological Systems (MPS) program, led by the National Center for Advancing Translational Sciences, is part of a joint effort on MPS development with the Defense Advanced Research Projects Agency and with regulatory guidance from FDA, is now in its final year of funding. The program has produced many tangible outcomes in tissue chip development in terms of stem cell differentiation, microfluidic engineering, platform development, and single and multi-organ systems-and continues to help facilitate the acceptance and use of tissue chips by the wider community. As the first iteration of the program draws to a close, this Commentary will highlight some of the goals met, and lay out some of the challenges uncovered that will remain to be addressed as the field progresses. The future of the program will also be outlined. Impact statement This work is important to the field as it outlines the progress and challenges faced by the NIH Microphysiological Systems program to date, and the future of the program. This is useful information for the field to be aware of, both for current program stakeholders and future awardees and partners.