Carbon nanotubes (CNTs) are one of widely used nanomaterials in industry and biomedicine. The potential impact of single-walled carbon nanotubes (SWCNTs) was evaluated using Caenorhabditis elegans (C. elegans) as a toxicological animal model. SWCNTs are extremely hydrophobic to form large agglomerates in aqueous solutions. Highly soluble amide-modified SWCNTs (a-SWCNTs) were therefore used in the present study so that the exact impact of SWCNTs could be studied. No significant toxicity was observed in C. elegans due to the amide modification. a-SWCNTs were efficiently taken up by worms and caused acute toxicity, including retarded growth, shortened lifespan and defective embryogenesis. The resulting toxicity was reversible since C. elegans could recover from a-SWCNT-induced toxicity once the exposure terminates. Chronic exposure to low doses of a-SWCNTs during all development stages could also cause a toxic accumulation in C. elegans. Genome-wide gene expression analysis was performed to investigate the toxic molecular mechanisms. Functional genomic analysis and molecular biology validation suggest that defective endocytosis, the decreased activity of the citrate cycle and the reduced nuclear translocation of DAF-16 transcription factor play key roles in inducing the observed a-SWCNT toxicity in worms. The present study presents an integrated approach to evaluating the toxicity of nanomaterials at the organism and molecular level for human and environmental health and demonstrates that traditional toxicological endpoints associated with functional genomic analysis can provide global and thorough insight into toxicity.