A composition comprising: a double-stranded short interfering nucleic acid (siNA) molecule that modulates the expression and/or activity of a target RNA sequence via RNA interference, wherein the molecule has a passenger strand and a guide strand and comprises a structure represented by one of the following formulae to: wherein, (a) the upper strand is the passenger strand and the lower strand is the guide strand of the double-stranded nucleic acid molecule; the guide strand is complementary to the target sequence and the passenger strand is complementary to the guide strand, wherein one or more mismatches between the guide strand and passenger strand and/or between the guide strand and the target sequence are tolerated so long as RNAi activity is maintained; (b) each N is independently a nucleotide wherein one or more Ns may be substituted with a non-nucleotide moiety so long as RNAi activity is maintained; (c) each B 1, B 2, and B 3 is independently a terminal cap optionally including a ligand, polymer, protein or peptide transduction domain, nuclear localization sequence, cell penetrating peptide, receptor, steroid, vitamin, antibody, protamine, and/or hormone, optionally attached via a linker, wherein any of B 1, B 2, and/or B 3 is optionally absent; (d) x is an integer from 0 to 4, provided that when x is 1, 2, 3, or 4, one or more of the x nucleotides can be complementary to nucleotides in the target sequence, and one or more phosphorothioate internucleotide linkage(s) "s" can be present in the x region when x is 1, 2, 3, or 4; (e) y is an integer from 0 to 4, provided that when y is 1, 2, 3, or 4, one or more of the y nucleotides can be complementary to nucleotides in the target sequence, and one or more phosphorothioate internucleotide linkage(s) "s" can be present in the y region when y is 1, 2, 3, or 4; (f) N nucleotides of the guide strand are 2'-deoxy-2'-fluoro nucleotides and N nucleotides of the guide strand are 2'-O-methyl nucleotides, with an optional variance of 1 or 2 N or N nucleotides being tolerated provided that RNAi activity is maintained; (g) S is a phosphorothioate or phosphorodithioate internucleotide linkage, wherein S 1, S 2, and S 3 are required; and (h) N nucleotides of the passenger strand are independently selected from ribonucleotide, 2'-O-alkyl nucleotide, 2'-deoxy-2'-fluoro nucleotide, 2'-deoxy nucleotide, and LNA. (a) the upper strand is the passenger strand and the lower strand is the guide strand of the double-stranded nucleic acid molecule; the guide strand is complementary to the target sequence and the passenger strand is complementary to the guide strand, wherein one or more mismatches between the guide strand and passenger strand and/or between the guide strand and the target sequence are tolerated so long as RNAi activity is maintained; (b) each N is independently a nucleotide wherein one or more Ns may be substituted with a non-nucleotide moiety so long as RNAi activity is maintained; (c) each B 1, B 2, and B 3 is independently a terminal cap optionally including a ligand, polymer, protein or peptide transduction domain, nuclear localization sequence, cell penetrating peptide, receptor, steroid, vitamin, antibody, protamine, and/or hormone, optionally attached via a linker, wherein any of B 1, B 2, and/or B 3 is optionally absent; (d) x is an integer from 0 to 4, provided that when x is 1, 2, 3, or 4, one or more of the x nucleotides can be complementary to nucleotides in the target sequence, and one or more phosphorothioate internucleotide linkage(s) "s" can be present in the x region when x is 1, 2, 3, or 4; (e) y is an integer from 0 to 4, provided that when y is 1, 2, 3, or 4, one or more of the y nucleotides can be complementary to nucleotides in the target sequence, and one or more phosphorothioate internucleotide linkage(s) "s" can be present in the y region when y is 1, 2, 3, or 4; (f) N nucleotides of the guide strand are 2'-deoxy-2'-fluoro nucleotides and N nucleotides of the guide strand are 2'-O-methyl nucleotides, with an optional variance of 1 or 2 N or N nucleotides being tolerated provided that RNAi activity is maintained; (g) S is a phosphorothioate or phosphorodithioate internucleotide linkage, wherein S 1, S 2, and S 3 are required; and (h) N nucleotides of the passenger strand are independently selected from ribonucleotide, 2'-O-alkyl nucleotide, 2'-deoxy-2'-fluoro nucleotide, 2'-deoxy nucleotide, and LNA.