We showed that sepiolite can transfer DNA into mammalian cells, opening alluring avenues for biothechnological and biomedical applications. Importantly, mammalian cells spontaneously internalize sepiolite, facilitating the spontaneous transport and delivery of bound molecules, but increasing the risks of potential toxicity. In addition, the fibrous nature of sepiolite raised health concerns about possible asbestos-like effects, especially because sepiolite can transfer DNA into bacteria through Yoshida effect. In spite that extrapolations from bacteria to mammalian cells could correspond to over-interpretations and the classification by IARC as non-hazardous and non-carcinogenic, we addressed here the response of human cells to interactions with sepiolite. We tested three classical cell responses to stress. We show that mammalian cells respond to sepiolite exposure, inducing the production of reactive oxygen species and the expression of inflammatory cytokines. This shows that cells detect sepiolite contamination and respond. Remarkably, sepiolite exposure did not alter the cell cycle distribution and triggers neither the DNA damage response program nor apoptosis, suggesting that it does not significantly assault the genetic material in mammalian cells. The potential toxicity of chronic versus transient exposure to sepiolite is discussed.