Interstitial cystitis/bladder pain syndrome (IC/BPS) is a syndrome of unpleasant bladder sensations and lower urinary tract symptoms. The three main proposed etiologies are bladder urothelial dysfunction, bladder inflammation (possible neurogenic), and neuropathic pain. Despite decades of basic and clinical research, IC/BPS remains difficult to treat. A variety of treatments are used, each aimed towards one etiology. For example, glycosaminoglycans are thought to improve the urothelial permeability barrier, anti-inflammatory agents are used to decrease general inflammation, and mast cell stabilizers and/or antagonists of mast cell products are used in the treatment of neurogenic inflammation. In the (unfortunately frequent) event that a treatment fails, possible reasons are that (1) the clinician is aiming towards the wrong etiology for that patient (i.e., the treatment is off target) or (2) the correct etiology is being targeted, but the treatment is not ameliorating it (i.e., the treatment is sub-therapeutic). This is a crucial distinction, because an off-target treatment should be abandoned, but a sub-therapeutic treatment should be escalated. Currently, our inability to make this crucial distinction is the greatest obstacle to effective treatment. An important future advance would be to identify urine or serum biomarkers specific to each etiologic target. Then, each biomarker could be used to select appropriate patients for each treatment and monitor the treatment's effect on its intended target.