This invention relates to compounds, compositions, and methods useful for modulating gene expression using chemically modified double stranded nucleic acid molecules. In particular, the instant invention features double stranded nucleic acid molecules including small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules and methods used to modulate the expression of genes via RNA interference (RNAi). The invention features various modifications to double stranded nucleic acid structures, including chemically modified overhangs and optimized stabilization motifs of guide (antisense) strand and passenger (sense) strands of double stranded nucleic acid molecules that allow for potent RNA interference in therapeutically relevant applications.