During cap-dependent eukaryotic translation initiation, ribosomes scan messenger RNA from the 5′ end to the first AUG start codon with favourable sequence context^,. For many mRNAs this AUG belongs to a short upstream open reading frame (uORF), and translation of the main downstream ORF requires re-initiation, an incompletely understood process^,,,. Re-initiation is thought to involve the same factors as standard initiation^,,. It is unknown whether any factors specifically affect translation re-initiation without affecting standard cap-dependent translation. Here we uncover the non-canonical initiation factors density regulated protein (DENR) and multiple copies in T-cell lymphoma-1 (MCT-1; also called MCTS1 in humans) as the first selective regulators of eukaryotic re-initiation. mRNAs containing upstream ORFs with strong Kozak sequences selectively require DENR–MCT-1 for their proper translation, yielding a novel class of mRNAs that can be co-regulated and that is enriched for regulatory proteins such as oncogenic kinases. Collectively, our data reveal that cells have a previously unappreciated translational control system with a key role in supporting proliferation and tissue growth.