Programmable proteins to detect, visualize, modulate, or eliminate proteins of selection in vitro and in vivo are essential to study the targets recognized and the biology that follows. The specificity of programmable proteins can be easily altered by designing their sequences and structures. The flexibility and modularity of these proteins are currently pivotal for synthetic biology and various medical applications. There exist numerous reviews of the concept and application of individual programmable proteins, such as programmable nucleases, single-domain antibodies, and other protein scaffolds. This review proposes an expanded conceptual framework of such programmable proteins based on their programmable principle and target specificity to biomolecules (nucleic acids, proteins, and glycans) and overviews their advantages, limitations, and future directions.