Urothelial carcinoma (transitional cell carcinoma) is the most common malignancy of the urinary tract. Urothelial carcinoma of the bladder is a common disease but has traditionally been underrepresented in both public awareness and cancer research. The purpose of this review is to provide an outline of the recent updates in understanding of urothelial cancer etiology, particularly with regards to lower tract muscle-invasive disease, and to discuss the identified mutations in high- and low-grade disease. We will consider evidence for the current systemic therapies for muscle-invasive and metastatic disease and review the targeted therapies under investigation for advanced urothelial cancer.