Can machine learning crack the code in the nose? Over the past decade, studies tried to solve the relation between chemical structure and sensory quality with Big Data. These studies advanced computational models of the olfactory stimulus, utilizing artificial intelligence to mine for clear correlations between chemistry and psychophysics. Computational perspectives promised to solve the mystery of olfaction with more data and better data processing tools. None of them succeeded, however, and it matters as to why this is the case. This article argues that we should be deeply skeptical about the trend to black-box the sensory system’s biology in our theories of perception. Instead, we need to ground both stimulus models and psychophysical data on real causal-mechanistic explanations of the olfactory system. The central question is: Would knowledge of biology lead to a better understanding of the stimulus in odor coding than the one utilized in current machine learning models? That is indeed the case. Recent studies about receptor behavior have revealed that the olfactory system operates by principles not captured in current stimulus-response models. This may require a fundamental revision of computational approaches to olfaction, including its psychological effects. To analyze the different research programs in olfaction, we draw on Lloyd’s “Logic of Research Questions,” a philosophical framework which assists scientists in explicating the reasoning, conceptual commitments, and problems of a modeling approach in question.