Despite intense drug development in the last decade in metastatic urothelial carcinoma and the incorporation of novel compounds to the treatment armamentarium, chemotherapy remains a key treatment strategy for this disease. Platinum-based combinations are still the backbone of first-line therapy in most cases. The role of chemotherapy in the second line has been more ill-defined due to the complexity of this setting, where patient selection remains critical. Nevertheless, two regimens, one in monotherapy (i.e. vinflunine) and one in combination with antiangiogenics (i.e. docetaxel + ramucirumab) have shown efficacy. Immunotherapy through checkpoint inhibition has revealed remarkably durable benefit in a small proportion of patients in the first and second line and is currently the preferred partner for combinations with chemotherapy. Difficult populations such as patients with liver metastases or those progressing to checkpoint inhibition represent a medical challenge and selective ways of delivering cytotoxics, like the antibody–drug conjugates, might represent a valid alternative. This article reviews the current role of chemotherapy in the management of advanced urothelial carcinoma and the ongoing and coming studies involving this treatment strategy.