Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating urinary bladder condition that presents with a wide variety of clinical phenotypes. It is commonly characterized by persistent pelvic pain and lower urinary tract symptoms, such as urinary frequency and urgency. Current clinicopathological and genomic evidence has indicated that IC/BPS with Hunner lesions is a clinically relevant distinct subtype with proven bladder pathology of subepithelial chronic inflammatory changes that are characterized by enhanced local immune responses and epithelial denudation. However, other forms of IC/BPS lacking Hunner lesions are a symptom syndrome complex of non-inflammatory conditions with little evidence of bladder etiology, characterized by aberrant neural activity in neurotransmission systems which leads to central nervous sensitization with potential involvement of urothelial malfunction, or clinical presentation of somatic and/or psychological symptoms beyond the bladder. Given such distinct potential pathophysiology between IC/BPS subtypes, disease biomarkers of IC/BPS should be provided separately for subtypes with and without Hunner lesions. Tailored approaches that target characteristic immunological inflammatory processes and epithelial denudation for IC/BPS with Hunner lesions, or the sensitized/altered nervous system, urothelial malfunction, association with other functional somatic syndromes, and psychosocial problems for IC/BPS without Hunner lesions, are essential to identify optimal and reliable disease-specific IC/BPS biomarkers.