Microbes live in diverse communities yet their physiologies are typically studied in axenic culture. To begin to address this dichotomy, whole-genome microarray analyses were used and revealed that several major metabolic pathways were affected in Synechococcus sp. WH8102, a model phototroph, when grown with Vibrio parahaemolyticus, a model heterotroph. In co-cultures with V. parahaemolyticus, although phosphate was not depleted, Synechococcus sp. WH8102 may have experienced phosphate stress since the expression of phosphate acquisition genes increased and alkaline phosphatase activity was higher than in monocultures. Expression of cell wall synthesis genes and the components of a zinc transporter were also upregulated. In contrast, a ferric uptake regulation (Fur) family gene was downregulated as were genes that encode proteins rich in iron or involved in detoxifying oxygen radicals. Nitrogen use may also have been affected in co-cultures as the gene expression changes share similarities with ammonia-grown Synechococcus. This study demonstrates the multiple impacts that interspecific microbial interactions can have on the physiology of a major primary producer and the importance of investigating microbial physiology from a community perspective.