Neurogenic detrusor overactivity (NDO) is a complication of multiple sclerosis, spinal cord injury (SCI), stroke, head injury, and other conditions characterized by damage to the upper motor neuronal system. NDO often leads to high bladder pressure that may cause upper urinary tract damage and urinary incontinence (UI). Prior to the use of onabotulinumtoxinA, oral anticholinergics and surgical augmentation cystoplasty were the treatment options. Overactive bladder (OAB) is non-neurogenic and affects a much larger population than NDO. Both NDO and OAB negatively impact patients' quality of life (QOL) and confer high health care utilization burdens. Early positive results from pioneering investigators who injected onabotulinumtoxinA into the detrusor of patients with SCI caught the interest of Allergan, which then initiated collaborative clinical trials that resulted in FDA approval of onabotulinumtoxinA 200U in 2011 for NDO and 100U in 2013 for patients with OAB who inadequately respond to or are intolerant of an anticholinergic. These randomized, double-blind, placebo-controlled trials for NDO showed significant improvements in UI episodes, urodynamic parameters, and QOL; the most frequent adverse events were urinary tract infection (UTI) and urinary retention. Similarly, randomized, double-blind, placebo-controlled trials of onabotulinumtoxinA 100U for OAB found significant improvements in UI episodes, treatment benefit, and QOL; UTI and dysuria were the most common adverse events. Long-term studies in NDO and OAB showed sustained effectiveness and safety with repeat injections of onabotulinumtoxinA, the use of which has profoundly improved the QOL of patients failing anticholinergic therapy and has expanded the utilization of onabotulinumtoxinA into smooth muscle.