Retinal ganglion cells (RGCs) are the first cell type to be specified during vertebrate retinogenesis. Specification and differentiation of the RGC lineage are a stepwise process involving a hierarchical gene regulatory network. During the past decade, a framework of the network has emerged and key transcriptional regulators have been identified. Pax6, Notch, Ath5, and the Brn3 (Pou4f) factors act at different levels of the regulatory hierarchy. In this review, we summarize the current understanding of the functions of these and other transcriptional factors in the specification and differentiation of the RGC lineage. We emphasize the regulatory relationships among transcription factors at different steps of RGC development. We discuss critical issues that need to be addressed before a complete understanding of the gene regulatory network for RGC development can be achieved. Future directions in RGC development will inevitably rely on combined genetic and genomics approaches.