Developing recombinant protein pharmaceuticals has proved to be very challenging because of both the complexity of protein production and purification, and the limited physical and chemical stability of proteins. To overcome the instability barrier, proteins often have to be made into solid forms to achieve an acceptable shelf life as pharmaceutical products. The most commonly used method for preparing solid protein pharmaceuticals is lyophilization (freeze-drying). Unfortunately, the lyophilization process generates both freezing and drying stresses, which can denature proteins to various degrees. Even after successful lyophilization with a protein stabilizer(s), proteins in solid state may still have limited long-term storage stability. In the past two decades, numerous studies have been conducted in the area of protein lyophilization technology, and instability/stabilization during lyophilization and long-term storage. Many critical issues have been identified. To have an up-to-date perspective of the lyophilization process and more importantly, its application in formulating solid protein pharmaceuticals, this article reviews the recent investigations and achievements in these exciting areas, especially in the past 10 years. Four interrelated topics are discussed: lyophilization and its denaturation stresses, cryo- and lyo-protection of proteins by excipients, design of a robust lyophilization cycle, and with emphasis, instability, stabilization, and formulation of solid protein pharmaceuticals.