Early on, crystallography was a domain of mineralogy and mathematics and dealt mostly with symmetry properties and imaginary crystal lattices. This changed when Wilhelm Conrad Rontgen discovered X-rays in 1895, and in 1912, Max von Laue and his associates discovered that X-ray irradiated salt crystals would produce diffraction patterns that could reveal the internal atomic periodicity of the crystals. In the same year, the father-and-son team, Henry and Lawrence Bragg successfully solved the first crystal structure of sodium chloride and the era of modern crystallography began. Protein crystallography (PX) started some 20 years later with the pioneering work of British crystallographers. In the past 50-60 years, the achievements of modern crystallography and particularly those in PX have been due to breakthroughs in theoretical and technical advancements such as phasing and direct methods; to more powerful X-ray sources such as synchrotron radiation; to more sensitive and efficient X-ray detectors; to ever faster computers and to improvements in software. The exponential development of PX has been accelerated by the invention and applications of recombinant DNA technology that can yield nearly any protein of interest in large amounts and with relative ease. Novel methods, informatics platforms and technologies for automation and high-throughput have allowed the development of large-scale, high-efficiency macromolecular crystallography efforts in the field of structural genomics. Very recently, the X-ray free-electron laser sources and its applications in PX have shown great potential for revolutionizing the whole field again in the near future.