In this perspective paper, we examine possible premises of plasticity in the neural substrates underlying cognitive change. We take the special role of the medial temporal lobe as an anchoring point, but also investigate characteristics throughout the cortex. Specifically, we examine the dimensions of evolutionary expansion, heritability, variability of morphometric change, and inter-individual variance in myelination with respect to the plastic potential of different brain regions. We argue that areas showing less evolutionary expansion, lower heritability, greater variability of cortical thickness change through the lifespan, and greater inter-individual differences in intracortical myelin content have a great extent of plasticity. While different regions of the brain show these features to varying extent, analyses converge on the medial temporal lobe including the hippocampi as the target of all these premises. We discuss implications for effects of training on brain structures, and conditions under which plasticity may be evoked.