The initial steps in hemangioblast specification occur in the primitive streak during gastrulation and result in the generation of mesodermal precursors committed to the hematopoietic or endothelial lineages. The differentiation process involves the acquisition of a specialized phenotype that depends on the expression of lineage-specific genes and the repression of genes characteristic of multipotent progenitors and alternative lineages. This genetic program to coordinate hemangioblast development is controlled by the complex and dynamic interplay between signalling pathways and transcription factors. In this review, we focus on recent studies that have revealed transcription factors and signalling pathways that progressively direct cell fate choices during hemangioblast specification and commitment.