Much of what is known about tolerance of the lower urinary tract to radiation comes from experience treating pelvic malignancies with radiation. Effects of radiation on the bladder and urethra have been documented following treatment of various pelvic malignancies such as bladder, prostate, gynecologic, and anorectal cancers. Dose and degree of exposure vary with the site and method of treatment, ranging from bladder cancer, where a substantial portion of the bladder is deliberately targeted with external beam radiation, to prostate cancer, where both prostate and prostatic urethra are targeted and adjacent bladder tissue is incidentally exposed. There can be homogeneous or heterogeneous distribution of radiation dose depending on whether radiation is delivered as external beam therapy, brachytherapy (BT) or a combination of the two. Furthermore, radiation is often combined with chemotherapy, which can result in heightened sensitivity of normal tissue to radiation. Over the past decade, dose escalation studies in prostate cancer have shed light on the effects of higher radiation doses on the lower urinary tract. Toxicity can be divided into acute and long-term effects. In this chapter, we discuss the pathogenesis and clinical manifestation of lower urinary tract toxicity after exposure to radiation.