Transcriptomics is a powerful tool for elucidating the molecular mechanisms that underlie the ability of organisms to survive and thrive in dynamic and changing environments. Here, we review the major contributions in this field, and we focus on studies of mussels in the genus Mytilus, which are well-established models for the study of ecological physiology in fluctuating environments. Our review is organized into four main sections. First, we illustrate how the abiotic forces of the intertidal environment drive the rhythmic coupling of gene expression to diel and tidal cycles in Mytilus californianus. Second, we discuss the challenges and pitfalls of conducting transcriptomic studies in field-acclimatized animals. Third, we examine the link between transcriptomic responses to environmental stress and biogeographic distributions in blue mussels, Mytilus trossulus and Mytilus galloprovincialis. Fourth, we present a comparison of transcriptomic datasets and identify 175 genes that share common responses to heat stress across Mytilus species. Taken together, these studies demonstrate that transcriptomics can provide an informative snapshot of the physiological state of an organism within an environmental context. In a comparative framework, transcriptomics can reveal how natural selection has shaped patterns of transcriptional regulation that may ultimately influence biogeography.