Cell death is a prominent feature of the developing vertebrate nervous system, affecting neurons, glial cells and their progenitors. The most extensively studied and best understood phase of cell death occurs in populations of neurons shortly after they begin establishing connections with other neurons and/or non-neural tissues. This phase of cell death makes appropriate adjustments to the relative sizes of interconnected groups of neurons and matches the size of neuronal populations that innervate non-neural tissues to the optimal requirements of these tissues. The fate of neurons during this period of development is regulated by a variety of secreted proteins that either promote survival or bring about cell death after binding to receptors expressed on the neurons. These proteins may be derived from the targets the neurons innervate, the afferents they receive or from associated glial cells, or they may be secreted by the neurons themselves. In this review, I will outline the established and emerging principles that modulate neuronal number in the developing nervous system.