Zahir Friedman syndrome is a rare microdeletion neurodevelopmental disability disorder that was first discovered in 2007. It presents a complex developmental profile with developmental delay, intellectual disability, and/or autism spectrum disorder reported. A constellation of other system defects is also commonly found. Importantly, patients present with a subtle but distinctive facial gestalt that enables the identification of the syndrome when present along with the known causative genetic lesion. Both CHD8 and SUPT16H genes are considered causative for this syndrome as they are present in the commonly affected microdeletion region on chromosome 14q11.2. The syndrome occurs due to heterozygous loss of this critical region. Both CHD8 and SUPT16H are known to have important and wide-ranging activity in epigenomic regulatory processes. Notably, CHD8 is considered a master driver of autism, while it has recently emerged that SUPT16H functions in nucleosome organization and is highly intolerant to loss of function. In this entry, the presentation of ZFS from birth to adulthood, as well as the role of its causative genes, is discussed in detail.