Homeostatic synaptic scaling adjusts a neuron's excitatory synaptic strengths up or down to compensate for perturbations in activity. Little is known about the molecular pathway(s) involved, nor is it clear which aspect of "activity"-local synaptic signaling, postsynaptic firing, or large-scale changes in network activity-is required to induce synaptic scaling. Here, we selectively block either postsynaptic firing in individual neurons or a fraction of presynaptic inputs, while optically monitoring changes in synaptic strength. We find that synaptic scaling is rapidly induced by block of postsynaptic firing, but not by local synaptic blockade, and is mediated through a drop in somatic calcium influx, reduced activation of CaMKIV, and an increase in transcription. Cortical neurons thus homeostatically adjust synaptic strengths in response to changes in their own firing rate, a mechanism with the computational advantage of efficiently normalizing synaptic strengths without interfering with synapse-specific mechanisms of information storage.