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The very first step in the establishment of neuronal polarity consists of the gen-eration of a neurite from a spherical cell. Later, other neurites form, and typically one differentiates into the axon, while the remaining neurites become dendrites. The spatial selection of the site from which the first neurite emerges is a crucial develop-mental event, since (1) it determines the location from which the second neurite grows—at the diametrically opposite pole—creating a bipolar phenotype and (2) it confers to cultured hippocampal neurons some “preferred axon growth characteristics”.1 The bipolar phenotype is responsible for directed migration and thus, final positioning of cortical neurons, implying that any molecular defect in this first step of neuronal polarity will severely affect brain development, altering the final orientation and integration of neu-rons in the cortex. An essential question is to what extent the selection of the site where the first neurite forms is extrinsically or intrinsi-cally determined. The idea that neuronal polarity is established cell-autonomously derives from the observation that most isolated neurons in vitro can establish their first axon/dendritic polarity in the absence of asymmetric extracellular cues.2 However, it is also known that the asymmetric presence of external cues can influence the position of the axon.3,4 We believe that two recent publications from our laboratory5,6 help to clarify this ques-tion. The main findings and conclusions are summarized below. A number of extrinsic cues such as lam-inin, tenascin and N-cadherin are found in situ in the cortex and are likely to con-tribute to early neuronal development