Owing to the complex aetiology and the variable penetrance of cleft lip and/or palate (CL/P), understanding the molecular basis has been challenging. Recent reports have identified two independent biochemical pathways that will help to elucidate the underlying pathology. Fibroblast growth factor signalling, previously known for its involvement in craniofacial development, is now implicated in the genetic basis of both syndromic and non-syndromic CL/P. At the same time, an important role in lip and palate development is beginning to emerge for small ubiquitin-like modifier modification, a widely used posttranslational regulatory mechanism. Both of these pathways might interact with environmental risk factors for CL/P. Here we review their contribution to normal and abnormal orofacial development.