This paper considers the real-time detection of abrupt and persistent anomalies in high-dimensional data streams. The goal is to detect anomalies quickly and accurately so that the appropriate countermeasures could be taken in time before the system possibly gets harmed. We propose a sequential and multivariate anomaly detection method that scales well to high-dimensional datasets. The proposed method follows a nonparametric, i.e., data-driven, and semi-supervised approach, i.e., trains only on nominal data. Thus, it is applicable to a wide range of applications and data types. Thanks to its multivariate nature, it can quickly and accurately detect challenging anomalies, such as changes in the correlation structure. Its asymptotic optimality and computational complexity are comprehensively analyzed. In conjunction with the detection method, an effective technique for localizing the anomalous data dimensions is also proposed. The practical use of proposed algorithms are demonstrated using synthetic and real data, and in variety of applications including seizure detection, DDoS attack detection, and video surveillance.