Modern computer threats are far more complicated than those seen in the past. They are constantly evolving, altering their appearance, perpetually changing disguise. Under such circumstances, detecting known threats, a fortiori zero-day attacks, requires new tools, which are able to capture the essence of their behavior, rather than some fixed signatures. In this work, we propose novel universal anomaly detection algorithms, which are able to learn the normal behavior of systems and alert for abnormalities, without any prior knowledge on the system model, nor any knowledge on the characteristics of the attack. The suggested method utilizes the Lempel-Ziv universal compression algorithm in order to optimally give probability assignments for normal behavior (during learning), then estimate the likelihood of new data (during operation) and classify it accordingly. The suggested technique is generic, and can be applied to different scenarios. Indeed, we apply it to key problems in computer security. The first is detecting Botnets Command and Control (C&C) channels. A Botnet is a logical network of compromised machines which are remotely controlled by an attacker using a C&C infrastructure, in order to perform malicious activities. We derive a detection algorithm based on timing data, which can be collected without deep inspection, from open as well as encrypted flows. We evaluate the algorithm on real-world network traces, showing how a universal, low complexity C&C identification system can be built, with high detection rates and low false-alarm probabilities. Further applications include malicious tools detection via system calls monitoring and data leakage identification.