Biomolecules are essential in pharmaceuticals, biocatalysts, biomaterials, etc., but unfortunately they are extremely susceptible to extraneous conditions. When biomolecules meet porous organic frameworks, significantly improved thermal, chemical, and mechanical stabilities are not only acquired for raw biomolecules, but also molecule sieving, substrate enrichment, chirality property, and other functionalities are additionally introduced for application expansions. In addition, the intriguing synergistic effect stemming from elaborate and concerted interactions between biomolecules and frameworks can further enhance application performances. In this paper, the synthesis strategies of the so-called bio-organic frameworks (BOFs) in recent years are systematically reviewed and classified. Additionally, their broad applications in biomedicine, catalysis, separation, sensing, and imaging are introduced and discussed. Before ending, the current challenges and prospects in the future for this infancy-stage but significant research field are also provided. We hope that this review will offer a concise but comprehensive vision of designing and constructing multifunctional BOF materials as well as their full explorations in various fields.