IC patients are generally diagnosed by the presence of certain clinical criteria, such as the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) guidelines and American Urological Association (AUA) IC guidelines, in the absence of other identifiable causes for symptoms (e.g., urinary tract infection and cancer). Diagnosis of IC has thus far relied on urine cytology, invasive and painful cystoscopy with and without hydrodistention and/or bladder biopsy, and biofluid-based assays. However, cytology is not sufficiently specific. Cystoscopic appearance is normal in the majority of IC patients. In current clinical practice, diagnosis is not sensitive. Several groups have attempted to elucidate the pathophysiology of this condition. However, clear descriptions of disease indicators and studies of larger populations are still needed to contribute to our understanding of molecular and cellular mechanisms. In general, it takes repeated longitudinal assessment of cytology and cystoscopy over 4-5 years from the first visit to definitively diagnose IC. Bladder pain is a hallmark of IC although there is significant overlap in symptoms between IC and other urinary tract disorders such as overactive bladder (OAB). Because pain is influenced by subjective perceptions, differentiating IC from OAB is still a diagnostic challenge. Collectively, current diagnosis does not provide accuracy/validity and convenience. Thus, objective diagnostic markers are urgently needed for IC diagnosis.