Natural selection typically acts on multiple traits simultaneously. Quantitative genetics provides the theory for predicting the response to selection of multiple traits and predicts symmetrical responses to selection (the response to upward selection on both traits is equal to their response to downward selection). In reality, however, the response to simultaneous selection on two traits is often asymmetrical. We provide a physiology-based framework to explain the asymmetrical response to simultaneous selection on two important life history traits: body size and development time. The tobacco hornworm, Manduca sexta, is particularly well suited for such a study, as the physiological control of body size and development time is well known in this species. Three physiological factors control both life history traits in M. sexta: growth rate, the critical weight that measures the timing of the onset of the cessation of juvenile hormone secretion (which initiates the processes leading to pupation) and the time interval between the critical weight and secretion of the molting hormone 20-hydroxyecdysteroid (the interval to cessation of growth, ICG). Asymmetry in the response to simultaneous selection on the two life history traits is due to the different types of selection acting on the three physiological factors. The critical weight and ICG are always under synergistic selection when both focal traits are selected in the same direction and under antagonistic selection when the focal traits are selected in opposite directions. Growth rate follows the opposite pattern. We propose a general model to explain the asymmetric response to simultaneous selection. This model emphasizes the importance of physiological processes in understanding evolutionary responses to selection and the control of complex traits.