Whole-cell voltage-clamp is routinely employed to measure synaptic conductances involved in a variety of neuronal processes, but little attention has been given to the limitations of this approach. Here, we reveal that voltage-clamp is completely ineffective for dendritic spines, the locus of most excitatory synapses in the mammalian brain. Combining simple compartmental modeling with dendritic patch-clamp recordings and two-photon optical techniques, we find that the spine neck resistance prevents voltage control of synaptic events, leading to large spine depolarization. As a consequence, voltage-clamp both substantially underestimates synaptic conductance and allows the recruitment of voltage-gated channels. To provide new, accurate measurements of synaptic parameters, we develop an approach to estimate AMPA conductance at single spines. Our results in cortical layer 5 pyramidal neurons indicate that single synapse AMPA conductance is much larger (IQR: 0.96-2.53 nS) than previously appreciated. These findings question the utility of whole-cell voltage-clamp for analyzing synaptic transmission and plasticity.