The South African clawed frog (Xenopus laevis), a prominent vertebrate model in cell and developmental biology, has been instrumental in studying molecular mechanisms of neural development and disease. Recently, high-resolution mass spectrometry (HRMS), a bioanalytical technology, has expanded the molecular toolbox of protein detection and characterization (proteomics). This chapter overviews the characteristics, advantages, and challenges of this biological model and technology. Discussions are offered on their combined use to aid studies on cell differentiation and development of neural tissues. Finally, the emerging integration of proteomics and other 'omic technologies is reflected on to generate new knowledge, drive and test new hypotheses, and ultimately, advance the understanding of neural development during states of health and disease.