Small molecules such as amino acids (AAs) and metabolites are often treated as chemically simple species that either remain soluble or crystallize directly into ordered solids. Growing evidence challenges this view, revealing that many metabolites populate rich assembly landscapes containing oligomers and amyloid‐like fibrils that bridge the gap between monomers and crystals. Far from being transient curiosities, these intermediate states can encode structural information that shapes toxicity, polymorph selection, catalysis, and disease progression. In this review, we explore how analytical mass spectrometry (MS), particularly ion mobility spectrometry–MS (IMS–MS) and MS‐coupled ion spectroscopy, has opened a window onto these otherwise hidden assemblies. We show how IMS–MS resolves heterogeneous populations, captures early nucleation events, and exposes the decisive roles of charge balance, counterions, and additives in steering assembly pathways. Through representative examples spanning AAs and metabolites linked to amyloid formation and pathological crystallization, we argue that fibrillar intermediates can serve as deterministic waypoints rather than kinetic dead ends. We also confront the current limits of structural MS, from charge‐induced bias to spectral congestion and modeling challenges, and highlight emerging solutions enabled by gentler ion handling, cryogenic spectroscopy, multidimensional IMS, and data‐driven computation. Together, these advances transform MS from a passive observer into an active guide for discovering and predicting order in small‐molecule assemblies.
Thanh D. Do (Sun,) studied this question.