Jellyfish venoms are complex mixtures of bioactive proteins that disrupt key physiological processes in prey and predators. However, humans are also sensitive to the actions of jellyfish venoms and can develop mild to potentially fatal systemic reactions. The Atlantic sea nettle, Chrysaora quinquecirrha, is a venomous jellyfish that inflicts painful stings to humans. Experimental studies have demonstrated the toxicity of its venom on erythrocytes, cardiocytes, hepatocytes, nerve and muscle preparations. Yet knowledge is still lacking about its toxin repertoire and the contribution of individual venom components to overall toxicity. In this study, we used a combined transcriptomic/proteomic approach to identify potential toxin proteins in C. quinquecirrha venom. Mass spectral data from proteomics experiments on C. quinquecirrha venom were matched against a set of annotated protein sequences generated from a de novo C. quinquecirrha tentacle transcriptome. From this analysis, a wide variety of potential toxins were identified including hydrolases (proteases, lipases, glycoside hydrolases and acid anhydride hydrolases), transferases, cysteine-rich secretory proteins (venom allergens and protease inhibitors) and pore-forming toxins. Examination of the crude venom in vitro confirmed that C. quinquecirrha venom elicits cytotoxic, cytolytic and enzymatic activities, although results suggested that enzymes play a relatively minor role compared to potential pore-forming toxins or other cytotoxic/cytolytic proteins yet to be characterised. These results illustrate the utility of using an integrated approach to identify potential toxins and the selection of specific assays to characterise relevant proteins associated with the toxic effects of venom.