Nucleic acid-based therapy has shown great promise in accelerating bone regeneration as well as other diseases. Nucleic acids used in gene therapy mainly are either plasmid DNA (pDNA) or RNAs. Although pDNA therapy has been extensively studied for decades with encouraging preclinical and clinical results, side effects, and low efficiency associated with nuclear trafficking are hard to bypass. Unlike pDNA, RNAs (mRNA, siRNA, miRNA) exert their function in the cytoplasm, thereby being more efficient in hard-to-transfect cells such as primary osteoblasts. RNA interference-based gene silencing represents a negative regulation which knockdown the expression of antagonists that impair osteogenesis process. In contrary, mRNA therapy for osteogenesis represents a positive regulation which delivers mRNA encoding growth factors to accelerate bone regeneration. This review presents a comprehensive summary of the mRNA and siRNA-based therapies and the targets for bone re-generation in case of bone defect and osteoporosis.