Single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) are nanomaterials with one or multiple layers of carbon sheets. While it is suggested that various properties influence their toxicity, the specific mechanisms are not completely known. This study was aimed to determine if single or multi-walled structures and surface functionalization influence pulmonary toxicity and to identify the underlying mechanisms of toxicity. Female C57BL/6J BomTac mice were exposed to a single dose of 6, 18, or 54 μg/mouse of twelve SWCNTs or MWCNTs of different properties. Neutrophil influx and DNA damage were assessed on days 1 and 28 post-exposure. Genome microarrays and various bioinformatics and statistical methods were used to identify the biological processes, pathways and functions altered post-exposure to CNTs. All CNTs were ranked for their potency to induce transcriptional perturbation using benchmark dose modelling. All CNTs induced tissue inflammation. MWCNTs were more genotoxic than SWCNTs. Transcriptomics analysis showed similar responses across CNTs at the pathway level at the high dose, which included the perturbation of inflammatory, cellular stress, metabolism, and DNA damage responses. Of all CNTs, one pristine SWCNT was found to be the most potent and potentially fibrogenic, so it should be prioritized for further toxicity testing.