Protein synthesis is tightly regulated, and its dysregulation can contribute to the pathology of various diseases, including cancer. Increased or selective translation of mRNAs can promote cancer cell proliferation, metastasis and tumor expansion. Translational control is one of the most important means for cells to quickly adapt to environmental stresses. Adaptive translation involves various alternative mechanisms of translation initiation. Upstream open reading frames (uORFs) serve as a major regulator of stress-responsive translational control. Since recent advances in omics technologies including ribo-seq have expanded our knowledge of translation, we discuss emerging mechanisms for uORF-mediated translation regulation and its impact on cancer cell biology. A better understanding of dysregulated translational control of uORFs in cancer would facilitate the development of new strategies for cancer therapy.