We define the notion of one-shot signatures, which are signatures where any secret key can be used to sign only a single message, and then self-destructs. While such signatures are of course impossible classically, we construct one-shot signatures using quantum no-cloning. In particular, we show that such signatures exist relative to a classical oracle, which we can then heuristically obfuscate using known indistinguishability obfuscation schemes. We show that one-shot signatures have numerous applications for hybrid quantum/classical cryptographic tasks, where all communication is required to be classical, but local quantum operations are allowed. Applications include one-time signature tokens, quantum money with classical communication, decentralized blockchain-less cryptocurrency, signature schemes with unclonable secret keys, non-interactive certifiable min-entropy, and more. We thus position one-shot signatures as a powerful new building block for novel quantum cryptographic protocols.