Mutations in IQSEC2, a guanine nucleotide exchange factor for the ADP-ribosylation factor (Arf) family of small GTPases have recently been shown to cause non-syndromic X-linked intellectual disability (ID), characterised by substantial limitations in intellectual functioning and adaptive behaviour. This discovery was revealed by a combination of large-scale resequencing of the X chromosome, and key functional assays that revealed a reduction, but not elimination, of IQSEC2 GEF activity for mutations affecting conserved amino acids in the IQ-like and Sec7 domains. Compromised GTP binding activity of IQSEC2 leading to reduced activation of selected Arf substrates (Arf1, Arf6) is expected to impact on cytoskeletal organization, dendritic spine morphology and synaptic organisation. This study highlights the need for further investigation of the IQSEC gene family and Arf GTPases in neuronal morphology and synaptic function, and suggests that the genes encoding the ArfGEFs IQSEC1 and IQSEC3 should be considered as candidates for screening in autosomal ID.