Malformations of cortical development (MCDs) are heterogeneous disorders caused by abnormalities of cell proliferation, apoptosis, cell migration, cortical organization, and axon pathfinding. In severe MCDs, the cerebral cortex can appear completely disorganized, or may be replaced by aberrant laminar patterns, as in "4-layered" types of lissencephaly and polymicrogyria. Little is known about the abnormal layers in MCDs and whether they bear any relation to normal cortical layers or how MCDs affect specific neuron types. Normally, each layer contains a defined mixture of different types of pyramidal and nonpyramidal neurons. The neuron types are distinguished by molecular expression as well as morphologic, neurochemical, and electrophysiologic criteria. Patterns of layer-specific mRNA and protein expression reflect the segregation of different neuron types into different layers (e.g. corticospinal projection neurons in layer V). Numerous layer-specific markers have been described in rodent cortex, and increasing numbers are being documented in human and monkey cortex. Applied to MCDs, layer-specific markers have the potential to reveal new insights on pathogenesis, treatment possibilities, and genotype-phenotype correlations. However, much work remains before layer-specific markers become practical tools in diagnostic neuropathology. Additional markers, more extensive documentation of normal expression, and better antibodies compatible with paraffin-embedded tissues will be necessary.