A general view in philosophy of science says that the appropriateness of an object to act as a surrogate depends on the user’s decision to utilize it as such. This paper challenges this claim by examining the role of surrogative reasoning in high-throughput sequencing technologies (technology-driven surrogates) as they are used in contemporary microbiome science. Drawing on this, we argue that, in technology-driven surrogates, knowledge about the type of inference practically permitted and epistemically justified by the surrogate constrains their use and thus puts a limit to the user’s intentions to use any object as a surrogate for what they please. Ignoring this leads to a serious epistemic misalignment, which ultimately prevents surrogative reasoning. Thus, we conclude that knowledge about the type of surrogate reasoning that the technologies being used allow is fundamental to avoid misinterpreting the consequences of the data obtained with them, the hypothesis this data supports, and what these technologies are surrogates of.