MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) can both inhibit mRNA expression, but through different mechanisms. MiRNAs are endogenously encoded small noncoding RNAs derived from RNA hairpins, while siRNAs are derived from long double-stranded RNAs, often exogenous. MiRNAs typically inhibit translation by partially complementary target sequences, whereas siRNAs degrade mRNAs with fully complementary sequences. This study shows that an endogenously encoded human miRNA can cleave mRNAs with fully complementary target sites, while an exogenous siRNA inhibits mRNA expression without causing cleavage when targets are partially complementary. These findings suggest that miRNAs and siRNAs may use similar mechanisms to repress mRNA expression, with the choice of mechanism depending on the degree of target sequence complementarity. The study demonstrates that human miRNAs can induce mRNA cleavage when expressed endogenously or overexpressed, while synthetic siRNAs can inhibit mRNA translation without causing cleavage. This indicates that miRNAs and siRNAs may be functionally interchangeable in some contexts. The results support the hypothesis that miRNAs and siRNAs can interact with mRNA in similar ways, with the outcome determined by the level of complementarity between the RNA target and the RNA molecule. The study also shows that miRNAs and siRNAs may use similar ribonucleoprotein complexes for their functions, with the outcome depending on the complementarity of the target sequence. The findings suggest that miRNAs and siRNAs can both lead to mRNA degradation or translational inhibition, depending on the target sequence complementarity. The study highlights the importance of target sequence complementarity in determining the mechanism of mRNA repression by miRNAs and siRNAs.MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) can both inhibit mRNA expression, but through different mechanisms. MiRNAs are endogenously encoded small noncoding RNAs derived from RNA hairpins, while siRNAs are derived from long double-stranded RNAs, often exogenous. MiRNAs typically inhibit translation by partially complementary target sequences, whereas siRNAs degrade mRNAs with fully complementary sequences. This study shows that an endogenously encoded human miRNA can cleave mRNAs with fully complementary target sites, while an exogenous siRNA inhibits mRNA expression without causing cleavage when targets are partially complementary. These findings suggest that miRNAs and siRNAs may use similar mechanisms to repress mRNA expression, with the choice of mechanism depending on the degree of target sequence complementarity. The study demonstrates that human miRNAs can induce mRNA cleavage when expressed endogenously or overexpressed, while synthetic siRNAs can inhibit mRNA translation without causing cleavage. This indicates that miRNAs and siRNAs may be functionally interchangeable in some contexts. The results support the hypothesis that miRNAs and siRNAs can interact with mRNA in similar ways, with the outcome determined by the level of complementarity between the RNA target and the RNA molecule. The study also shows that miRNAs and siRNAs may use similar ribonucleoprotein complexes for their functions, with the outcome depending on the complementarity of the target sequence. The findings suggest that miRNAs and siRNAs can both lead to mRNA degradation or translational inhibition, depending on the target sequence complementarity. The study highlights the importance of target sequence complementarity in determining the mechanism of mRNA repression by miRNAs and siRNAs.