This review compares the therapeutic potential of small interfering RNAs (siRNAs) and microRNAs (miRNAs) in gene silencing. Both siRNAs and miRNAs are noncoding RNAs that play crucial roles in gene regulation by targeting messenger RNAs (mRNAs) at the post-transcriptional level. While siRNAs are highly specific to a single mRNA target, miRNAs can target multiple mRNAs. The mechanisms of action and clinical applications of siRNAs and miRNAs differ significantly. SiRNAs are designed to be fully complementary to their target mRNAs, leading to specific gene silencing through the RNA-induced silencing complex (RISC). MiRNAs, on the other hand, bind partially complementary to their target mRNAs, leading to translational repression, degradation, or cleavage. The review discusses the design of therapeutic siRNAs and miRNAs, including sequence selection, chemical modifications, and delivery strategies. Challenges such as off-target effects, immune responses, and poor stability are addressed, with strategies to mitigate these issues. The review also highlights the progress in clinical trials for siRNA and miRNA therapeutics, noting that siRNAs have advanced more rapidly due to their established experience in nucleic acid-based therapies.This review compares the therapeutic potential of small interfering RNAs (siRNAs) and microRNAs (miRNAs) in gene silencing. Both siRNAs and miRNAs are noncoding RNAs that play crucial roles in gene regulation by targeting messenger RNAs (mRNAs) at the post-transcriptional level. While siRNAs are highly specific to a single mRNA target, miRNAs can target multiple mRNAs. The mechanisms of action and clinical applications of siRNAs and miRNAs differ significantly. SiRNAs are designed to be fully complementary to their target mRNAs, leading to specific gene silencing through the RNA-induced silencing complex (RISC). MiRNAs, on the other hand, bind partially complementary to their target mRNAs, leading to translational repression, degradation, or cleavage. The review discusses the design of therapeutic siRNAs and miRNAs, including sequence selection, chemical modifications, and delivery strategies. Challenges such as off-target effects, immune responses, and poor stability are addressed, with strategies to mitigate these issues. The review also highlights the progress in clinical trials for siRNA and miRNA therapeutics, noting that siRNAs have advanced more rapidly due to their established experience in nucleic acid-based therapies.