Dendritic spines are morphologically and functionally heterogeneous. To understand this diversity, we use two-photon imaging of layer 5 neocortical pyramidal cells and measure action potential-evoked [Ca(2+)]i transients in spines. Spine calcium kinetics are controlled by (i) the diameter of the parent dendrite, (ii) the length of the spine neck, and (iii) the strength of spine calcium pumps. These factors produce different calcium dynamics in spines from basal, proximal apical, and distal apical dendrites, differences that are more pronounced without exogenous buffers. In proximal and distal apical dendrites, different calcium dynamics correlate with different susceptibility to synaptic depression, and modifying calcium kinetics in spines changes the expression of long-term depression. Thus, the spine location apparently determines its calcium dynamics and synaptic plasticity. Our results highlight the precision in design of neocortical neurons.