It is widely believed that content-signature-based intrusion detection systems (IDSes) are easily evaded by polymorphic worms, which vary their payload on every infection attempt. In this paper, we present Polygraph, a signature generation system that successfully produces signatures that match polymorphic worms. Polygraph generates signatures that consist of multiple disjoint content substrings. In doing so, Polygraph leverages our insight that for a real-world exploit to function properly, multiple invariant substrings must often be present in all variants of a payload; these substrings typically correspond to protocol framing, return addresses, and in some cases, poorly obfuscated code. We contribute a definition of the polymorphic signature generation problem; propose classes of signature suited for matching polymorphic worm payloads; and present algorithms for automatic generation of signatures in these classes. Our evaluation of these algorithms on a range of polymorphic worms demonstrates that Polygraph produces signatures for polymorphic worms that exhibit low false negatives and false positives.