We aim to establish a robust and comprehensive methodology for the de novo chemical synthesis of proteins with arbitrarily designed structures, endowing them with the capacity to transcend the constraints of biology. Such synthetic proteins—structurally well-defined organic compounds composed of diverse, linearly arranged building blocks yet capable of folding into intricate three-dimensional architectures—constitute a unique class of functional molecules, whose full application potential remains to be unlocked through the creative power of synthetic chemistry. Central to this methodology is the peptide hydrazide ligation reaction pioneered by our group—a widely adopted chemical strategy that enables the bottom-up synthesis of target proteins via convergent condensation of synthetic peptides prepared from tailor-made small-molecule residues. Three pivotal technologies are continuously consolidating and expanding this hydrazide-based methodology, progressively extending its scope to encompass nearly all protein targets: (1) reversible auxiliary strategies that overcome the challenges associated with protein solubilization and folding; (2) designer protein ligases that maximize reaction efficiency during the assembly of multidomain proteins; (3) robotic protein synthesizers that increasingly integrate more advanced AI to accelerate chemical protein synthesis. Using this methodology, we design and synthesize an ever-expanding repertoire of synthetic—and often “beyond-biology”—proteins across an unbounded chemical space, while proactively exploring their applications both as tools for interrogating disease mechanisms and drug actions, and as candidates for the development of protein-based therapeutics and products. Ultimately, physical-world data generated from these chemically synthesized “beyond-biology” proteins are being harnessed to drive the iterative evolution of a universal AI model capable of accommodating any conceivable protein structure—opening a new chapter in protein applications for human welfare.