Small open reading frames (smORFs) encoding polypeptides of less than 100 amino acids in eukaryotes (50 amino acids in prokaryotes) were historically excluded from genome annotation. However, recent advances in genomics, ribosome footprinting, and proteomics have revealed thousands of translated smORFs in genomes spanning evolutionary space. These smORFs can encode functional polypeptides, or act as cis-translational regulators. Herein we review evidence that some smORF-encoded polypeptides (SEPs) participate in stress responses in both prokaryotes and eukaryotes, and that some upstream ORFs (uORFs) regulate stress-responsive translation of downstream cistrons in eukaryotic cells. These studies provide insight into a regulated subclass of smORFs and suggest that at least some SEPs may participate in maintenance of cellular homeostasis under stress.