Gravity is the one constant, ubiquitous force that has shaped life on Earth over its 4.8 billion years of evolution. But the sheer inescapability of Earth’s gravitational pull has meant that its influence on Earth’s organisms is difficult to study. Neutralization of the gravity vector (so-called simulated microgravity) by random movement in three-dimensional space is the best option for Earth-based experiments, with spaceflight alone offering the possibility to assess the effects of an extremely reduced gravitational field (microgravity). However, the technical constraints associated with spaceflight introduce complications that can compromise the interpretation of microgravity experiments. It can be unclear whether changes detected in these experiments reflect additional spaceflight-related stresses (temperature shifts, vibrational effects, radiation exposure, and so on) as opposed to the loss of gravitational force per se. In this issue, Herranz et al. (2010) report a careful study in which the effects of simulated and actual microgravity on gene expression in Drosophila melanogaster were compared and the effects of the flight-associated stresses on the microgravity responses were investigated. A striking finding emerged. The additional stresses associated with the spaceflight experiment altered the response to microgravity. Despite controlling for the effects of these stresses/constraints, the group found that responses to microgravity are much stronger in the stressed/constrained background than in its absence. This interaction of gravity with other environmental influences is a novel finding with important implications for microgravity research and other situations where multiple stress factors are combined.