Urothelial cancer (UC) is a common malignancy with unique biology displaying a high tendency to recur despite complete resection of the primary lesion. In approximately 80% of the patients, UC is a non-curable chronic disease, however in the remaining ~20% of patients, the disease can progress and cause death. Despite the fact that UC in the USA is common and responsible for 82,000 new cases and 18,000 patients die from this disease annually, almost nothing has changed in the last decade regarding the diagnosis and treatment of UC. Hence, there is a burning need for non-invasive biomarkers for screening and follow up as well as to develop novel treatment strategies for targeted therapy. Recently we have discovered that Semaphorin-3A is involved in UC and may serve as a biomarker or a potential druggable target for therapy. Herein we review the current knowledge about Semaphorin-3A in UC.