Body size profoundly affects many aspects of animal biology, including metamorphosis, allometry, size-dependent alternative pathways of gene expression, and the social and ecological roles of individuals. However, regulation of body size is one of the fundamental unsolved problems in developmental biology. The control of body size requires a mechanism that assesses size and stops growth within a characteristic range of sizes. Under normal growth conditions in Manduca sexta, the endocrine cascade that causes the brain to initiate metamorphosis starts when the larva reaches a critical weight. Metamorphosis is initiated by a size-sensing mechanism, but the nature of this mechanism has remained elusive. Here we show that this size-sensing mechanism depends on the limited ability of a fixed tracheal system to sustain the oxygen supply to a growing individual. As body mass increases, the demand for oxygen also increases, but the fixed tracheal system does not allow a corresponding increase in oxygen supply. We show that interinstar molting has the same size-related oxygendependent mechanism of regulation as metamorphosis. We show that low oxygen tension induces molting at smaller body size, consistent with the hypothesis that under normal growth conditions, body size is regulated by a mechanism that senses oxygen limitation. We also found that under poor growth conditions, larvae may never attain the critical weight but eventually molt regardless. We show that under these conditions, larvae do not use the critical weight mechanism, but instead use a size-independent mechanism that is independent of the brain. M ost species of animals experience determinate growth and stop growing within a characteristic range of body size (1-4). This raises the question of how body size is sensed such that it is regulated within this range. How body size is sensed remains one of the fundamental unsolved problems in developmental biology.In insect larvae, the signal to stop growing and initiate a molt is the secretion of the steroid hormone ecdysone. Larval-larval molts are caused by pulses of ecdysone, and in the last larval stage of the tobacco hornworm, Manduca sexta, ecdysone causes the larva to stop feeding and initiate metamorphosis (5). The timing of ecdysone secretion is determined by the critical weight (6-9), a size threshold at which the endocrine events that eventually result in the cessation of feeding, entry into the wandering stage, and metamorphosis are initiated. The discovery of the critical weight demonstrated that initiation of the metamorphic molt depends not on instar duration or growth rate, but rather on size.The time course of these endocrine events is independent of further nutrition and growth. Therefore, the critical weight can be operationally assessed as the weight at which nutrition is no longer necessary for a normal time course to the cessation of feeding, entry into the wandering stage, and the pupal molt (5, 6, 9). The weight that we measure is a proxy for a physiological variable that is correlated w...