There is an increasing consensus that the locator/identifier separation of IP address is necessary to resolve the scalability issues of current Internet routing architecture. After identifiers are separated from locators, an identifier-to-locator mapping service must be employed to map identifiers onto locators. From this point, this paper proposes an anomaly detection and response approach based on mapping requests. By using the cumulative sum algorithm for change point detection, this approach introduces the anomalous traffic detection of mapping requests to diagnose the aberrant network behaviors. Once alarming, two effective response methods can be chosen to control the anomalous attack traffic in real time. Furthermore, in order to decouple the mapping request traffic from the mapping cache, this approach not only takes into account the mapping cache timeout but also puts forward a practical mapping request threshold algorithm. In particular, our simulation results show that, compared with the anomaly detection approach based on network traffic, the proposed approach is more advantageous and efficient. In addition, we also discuss the possible false positive and false negative problems, which may be caused by some accidental phenomena.