BACKGROUND CONTEXT: Small leucine-rich proteoglycans (SLRPs) play an essential role in extracellular matrix (ECM) organization and function. Recently, dysregulation of SLRPs has been implicated in degenerative disc disease (DDD). An in-depth analysis using high-throughput proteomic sequencing might provide valuable information on their implications in health and disease. PURPOSE: To utilize proteomics for analyzing the expression of SLRPs in fetal, healthy adult, and degenerated discs, to identify possible molecular targets to halt or reverse the degenerative process. STUDY DESIGN: Experimental analysis. METHODS: Proteomic signatures of 8 magnetic resonance imaging (MRI) normal lumbar discs (ND) [harvested from brain dead alive organ donors] were compared to 8 fetal disc samples (FD) [harvested from fetal spines devoid of congenital anomalies following spontaneous or medical termination of pregnancy] and 8 degenerate discs (DD) [collected from patients undergoing fusion surgery]. The various functional pathways along with the differential expression of SLRPs and the associated changes in collagens, large proteoglycans (LLRPs), matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been analyzed further using bioinformatics. This project was self-funded by the Ganga Orthopedic Research and Education Foundation. RESULTS: ESI-LC-MS/MS analysis revealed a total of 1,029 proteins in FD, 1,785 proteins in ND, and 1,775 proteins in DD. Fetal disc proteins were engaged mainly in ribosomal pathways (indicating active proliferation and regenerative potential). The healthy adult discs (ND) primarily participated in ECM maintenance and basic metabolic pathways, whereas the unique proteins of DD group were involved in inflammatory (Complement and coagulation cascades, Systemic Lupus Erythematosus and Leukocyte transendothelial migration) pathways and infective (Staphylococcus aureus infection, Prion diseases, Amoebiasis, Pertussis, and Legionellosis) channels which favor the recent concepts of inflammaging and subclinical infection as causes of DDD. Analysis of SLRPs revealed the upregulation of Biglycan in FDs and downregulation of Lumican, Decorin, Prolargin, and Chondroadherin in the DD group. The universal decrease in the abundance of SLRPs in the DD group was associated with an increase in MMPs and a reduction in TIMPs, collagen and LLRP content. CONCLUSIONS: Our study documents the influence of SLRPs in the maintenance of disc health and also the need for future research in using them for disc regeneration. CLINICAL SIGNIFICANCE: The various SLRPs that we identified are all known to have a beneficial influence on ECM integrity and a negative effect on the degenerative process at different stages in the evolution of degeneration. Biglycan, which is abundantly present in a fetus, may be suitable for regenerative therapy, and the other SLRPs like Lumican, Prolargin, Decorin, and Chondroadherin may serve the same purpose and/or as biomarkers.