Initialization and read-out of coupled quantum systems are essential ingredients for the implementation of quantum algorithms(1,2). Single-shot read-out of the state of a multi-quantum-bit (multi-qubit) register would allow direct investigation of quantum correlations (entanglement), and would give access to further key resources such as quantum error correction and deterministic quantum teleportation(1). Although spins in solids are attractive candidates for scalable quantum information processing, their single-shot detection has been achieved only for isolated qubits(3-6). Here we demonstrate the preparation and measurement of a multi-spin quantum register in a low-temperature solid-state system by implementing resonant optical excitation techniques originally developed in atomic physics. We achieve high-fidelity read-out of the electronic spin associated with a single nitrogen-vacancy centre in diamond, and use this read-out to project up to three nearby nuclear spin qubits onto a well-defined state(7). Conversely, we can distinguish the state of the nuclear spins in a single shot by mapping it onto, and subsequently measuring, the electronic spin(5,8). Finally, we show compatibility with qubit control: we demonstrate initialization, coherent manipulation and single-shot read-out in a single experiment on a two-qubit register, using techniques suitable for extension to larger registers. These results pave the way for a test of Bell's inequalities on solid-state spins and the implementation of measurement-based quantum information protocols.