Cryo-electron tomography (cryo-ET) allows researchers to visualize near-native cellular ultrastructure and determine the precise localization and in situ structure of increasingly challenging target proteins [1]. The power of cryo-ET lies in its ability to bridge cellular and structural biology. Correlating protein structure with nanometer-scale localization and cellular context promises to reveal how the structures of proteins at the atomic scale control biochemistry in situ and are influenced in turn by the cellular environment. Despite this promise, many challenges remain before cryo-ET can be applied to any target protein in a cell [2]. Cryo-ET of unstained biological samples relies on phase contrast by weakly electron scattering biomolecules to simultaneously visualize all proteins and other biological material in a sample [3, 4]. The challenge is then to identify a specific target protein within an often-complex cellular environment. This is made more difficult by the limited signal-to-noise ratio of cryo-tomograms, the presence of structurally similar non-target proteins, and artifacts introduced during sample preparation, image formation, and processing [3]. The result is that the most tractable proteins to identify in a tomogram are abundant, high molecular weight (>100 kDa) proteins with structures that are known from other methods and/or distinctive at low resolution [∗2, 5]. A majority of protein species in the cell do not meet these criteria and are instead relatively small (on average ∼50 kDa) and share similar structural envelopes at the nominal resolution of a single tomogram (2–5 nm) [6, 7]. To identify this second population of proteins within a tomogram, it remains necessary to apply molecular labels that serve as fiducial markers, guiding the localization of target proteins that are not readily identifiable. Here, I will describe considerations for designing labeling systems for cryo-ET and provide recent examples, with a focus on labels that do not require correlation with another imaging modality (e.g. correlative light and electron microscopy).