The natural history of non-muscle invasive bladder cancer is characterized by a 
high probability of recurrence and in the case of high-grade tumors, progression 
to muscle invasive cancer. This mandates a follow-up strategy designed to 
identify recurrences in the bladder early in their evolution in order to 
facilitate early intervention and ablation. Urine cytology is considered the 
gold standard urine biomarker. Although specificity exceeds 90% to 95%, its 
overall sensitivity ranges from 40% to 60% in expert hands and is both tumor 
grade and operator dependent. While cytology is an excellent test for detection 
of high-grade disease, the sensitivity is particularly weak for the detection of 
low grade tumors. This has spawned an entire field of research of in vitro 
diagnostic tests and cell-based assays in order to improve the diagnostic 
accuracy for detection of incident or recurrent disease. To date, the US Food 
and Drug Administration approved dipstick and immunoassays marketed as 
point-of-care tests. The point-of-care tests are intended for use as an adjunct 
to cystoscopy and cytology, and may have a role in the office evaluation of 
hematuria patients. Monoclonal antibody-based tests combined with cytology may 
improve the diagnostic accuracy and are superior to cytology alone. A recently 
approved cell-based assay, utilizing fluorescent in situ hybridization 
technology, may help resolve suspicious cytologies, and provide early and 
additional information about the biology of the bladder urothelium beyond that 
provided by cytology, a marker of disease relatively late in evolution. Novel 
promising markers are in various stages of clinical testing, and a panel of 
biomarkers may serve in the future as a feasible alternative to urine cytology 
and cystoscopy for the screening, detection, and follow-up of non-muscle 
invasive bladder cancer.