The complex computing systems employed by governments, corporations, and other institutions are frequently targeted by cyber-attacks designed for espionage and sabotage. The malicious software used in such attacks are typically custom-designed or obfuscated to avoid detection by traditional antivirus software. Our goal is to create a malware detection system that can quickly and accurately detect such otherwise difficult-to-detect malware. We pose the problem of malware detection as a multi-channel change-point detection problem, wherein the goal is to identify the point in time when a system changes from a known clean state to an infected state. We present a host-based malware detection system designed to run at the hypervisor level, monitoring hypervisor and guest operating system sensors and sequentially determining whether the host is infected. We present a case study wherein the detection system is used to detect various types of malware on an active web server under heavy computational load.