Due to their intrinsic differentiation potential, human pluripotent stem cells (hPSCs) hold remarkable promise for their use in cell-based therapies as well as an in vitro model for early human embryogenesis and for modeling disease. During the development of the human embryo, transient structures such as the neural crest (NC) and the cranial placodes (CPs) are specified in the first 3-4 weeks of gestation. Because of this early occurrence and a scarce availability of embryos for research purposes, these transient structures remain largely unexplored in humans. Hence, investigators are now exploiting in vitro differentiation of hPSC to unveil these early events and to generate NC and CP cells in vitro. Derivatives of the NC and CPs will contribute to the formation of very important organs, including most of the peripheral nervous system (NC) and the sensory organs of the head (CP). There are many diseases and conditions that affect NC and CP derivatives, thus a better knowledge of how these structures specialize, and the derivation of functional NC and CP cells for therapeutic applications will have an impact on the understanding and treatment of these disorders. Here, we discuss the current state of the art in directing hPSCs into NC or CP cells, which in spite of their importance is still in its infancy.