Abstract only Phosphorylation of eIF2 (eIF2‐P) lowers protein synthesis to conserve resources and facilitate preferential translation of specific transcripts that promote adaptation to environmental stresses. Central to the mechanisms of preferential translation are upstream ORFs (uORFs) embedded within the 5′‐leaders of mRNAs, which serve as “bar codes” that help ribosomes determine the levels of translation of mRNA coding sequences (CDS) during eIF2‐P. We have been studying the functions of uORFs that demarcate translational control and the roles that these preferentially translated genes play in cell adaptation to stress. Preferentially translated GADD34 (PPP1R15A) and constitutively expressed CReP (PPP1R15B) each function to dephosphorylate eIF2‐P and restore protein synthesis. Both GADD34 and CReP mRNAs contain two upstream uORFs, and using biochemical and genetic approaches we show that distinct features of these uORFs are critical for differential CDS translation. In the absence of stress and low eIF2‐P, translation of an inhibitory uORF in GADD34 acts as a barrier by inefficient translation termination that prevents subsequent reinitiation at the GADD34 CDS. Induced eIF2‐P during stress directs ribosome bypass of the inhibitory uORF, leading to enhanced translation of the GADD34 CDS. By comparison, CReP expression occurs independent of eIF2‐P via an uORF that allows for translation reinitiation at the CReP CDS independent of stress conditions. Alterations in the GADD34 uORF not only affect the status of eIF2‐P and translational control, but also cell adaptation to stress. Translation of other preferentially translated genes also feature bypass of uORFs, although by mechanisms featuring different uORF properties. For example, bypass of a single uORF directs preferential translation of CHOP (DDIT3/GADD153), a transcription factor that triggers cell death during periods of extended stress. We discovered that the CHOP uORF serves to stall elongating ribosomes and prevent ribosome reinitiation at the downstream CHOP CDS. Deletion of the CHOP uORF increases the levels and alters the pattern of induced CHOP expression during eIF2‐P. Elevated CHOP expression leads to increased cell death in response to stress. Finally, we determined that bypass of uORFs in IBTKalpha enhances translation of the CDS in response to eIF2‐P. Elevated levels of IBTKalpha localize to endoplasmic reticulum exit sites and facilitate initiation of autophagy. These examples and others indicate that the proper mixing and matching of uORFs with distinct properties are central for directing gene‐specific translation during eIF2‐P. Preferentially translated genes are critical for the timing and extent of translation and transcription, and alter metabolism and reclamation processes such as autophagy, which together can determine cell survival during environmental stresses. Support or Funding Information NIH GM049164