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Standard genetic approaches, particularly useful in understanding monogenic diseases, are no longer sufficient as research attention shifts toward multifactorial outcomes. Here, we examine this progression through the lens of holoprosencephaly (HPE), a common human malformation involving incomplete forebrain division, and a classic example of an etiologically complex outcome. We relate the basic underpinning of HPE pathogenesis to critical cell\u2010cell interactions and signaling molecules discovered through embryological and genetic approaches in multiple model organisms, and discuss the role of the mouse model in functional examination of HPE\u2010linked genes. We then outline the most critical remaining gaps to understanding human HPE, including the conundrum of incomplete penetrance\/expressivity and the role of gene\u2010environment interactions. To tackle these challenges, we outline a strategy that leverages new and emerging technologies in multiple model systems to solve the puzzle of HPE.<\/jats:p>","DOI":"10.1002\/dvdy.41","type":"journal-article","created":{"date-parts":[[2019,4,17]],"date-time":"2019-04-17T03:59:37Z","timestamp":1555473577000},"page":"626-633","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A forebrain undivided: Unleashing model organisms to solve the mysteries of holoprosencephaly"],"prefix":"10.1002","volume":"248","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-7572","authenticated-orcid":false,"given":"Yevgenya","family":"Grinblat","sequence":"first","affiliation":[{"name":"Department of Integrative Biology University of Wisconsin  Madison Wisconsin"},{"name":"Department of Neuroscience University of Wisconsin  Madison Wisconsin"},{"name":"McPherson Eye Research Institute University of Wisconsin  Madison 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