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Eukaryotic transcription factors activate gene expression with their DNA-binding domains and activation domains. DNA- binding domains bind the genome by recognizing structurally related DNA sequences; they are structured, conserved, and predictable from protein sequences. Activation domains recruit chromatin modifiers, coactivator complexes, or basal tran- scriptional machinery via structurally diverse protein-protein interactions. Activation domains and DNA-binding domains have been called independent, modular units, but there are many departures from modularity, including interactions be- tween these regions and overlap in function. Compared to DNA-binding domains, activation domains are poorly under- stood because they are poorly conserved, intrinsically disor- dered, and difficult to predict from protein sequences. This review, organized around commonly asked questions, de- scribes recent progress that the field has made in under- standing the sequence features that control activation domains and predicting them from sequence.