Pruritus remains a significant problem facing dermatologists and can be associated with various dermatoses and systemic derangements. At times, one can treat the underlying cutaneous or systemic process to alleviate itch. However, it is frequently challenging to identify the cause of a patient's itch and, in this situation, even more difficult to manage the symptom effectively. In this article, the authors discuss the approach to a patient with generalized pruritus without clinically obvious dermatoses. They also addresses mechanisms and management modalities of itch in common systemic diseases, including cholestasis, uremia, and neuropathic dysfunction.