Although cyanobacteria produce a wide range of natural toxins that impact aquatic organisms, food webs, and water quality, the mechanisms of toxicity are still insufficiently understood. Here, we implemented a whole-genome expression microarray to identify pathways, gene networks, and paralogous gene families responsive to Microcystis stress in Daphnia pulex . Therefore, neonates of a sensitive isolate were given a diet contaminated with Microcystis to contrast with those given a control diet for 16 days. The microarray revealed 2247 differentially expressed (DE) genes (7.6% of the array) in response to Microcystis , of which 17% are lineage-specific (i.e., these genes have no detectable homology to any other gene in currently available databases) and 49% are gene duplicates (paralogues). We identified four pathways/gene networks and eight paralogous gene families affected by Microcystis . Differential regulation of the ribosome, including three paralogous gene families encoding 40S, 60S, and mitochondrial ribosomal proteins, suggests an impact of Microcystis on protein synthesis of D. pulex . In addition, differential regulation of the oxidative phosphorylation pathway (including the NADH:ubquinone oxidoreductase gene family) and the trypsin paralogous gene family (a major component of the digestive system in D. pulex ) could explain why fitness is reduced based on energy budget considerations.