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Transfer RNA (tRNA) have been harbingers of many paradigms in RNA biology. They are among the first recognized noncoding RNA (ncRNA) playing fundamental roles in RNA metabolism. Although mainly recognized for their role in decoding mRNA and delivering amino acids to the growing polypeptide chain, tRNA also serve as an abundant source of small ncRNA named tRNA fragments. The functional significance of these fragments is only beginning to be uncovered. Early on, tRNA were recognized as heavily post-transcriptionally modified, which aids in proper folding and modulates the tRNA:mRNA anticodon-codon interactions. Emerging data suggest that these modifications play critical roles in the generation and activity of tRNA fragments. Modifications can both protect tRNA from cleavage or promote their cleavage. Modifications to individual fragments may be required for their activity. Recent work has shown that some modifications are critical for stem cell development and that failure to deposit certain modifications has profound effects on disease. This review will discuss how tRNA modifications regulate the generation and activity of tRNA fragments.