Despite advancements in omics technologies, including proteomics and transcriptomics, identification of therapeutic targets remains challenging. Ligandomics recently emerged as a unique technology of functional proteomics for global profiling of cell-binding protein ligands. When applied to diseased versus healthy vasculatures, comparative ligandomics systematically maps novel disease-restricted ligands that allow selective targeting of pathological but not physiological pathways, providing high efficacy with intrinsic safety. In this review, we discuss the potential of cellular ligands as therapeutic targets and summarize the development of ligandomics. We further compare the advantages and limitations of different omics technologies for drug target discovery and discuss target selection criteria to improve drug R&D success rates.
