A nuclease comprising: (i) a DNA-binding domain that binds to a target site in the genome of the cell; and (ii) a polypeptide comprising an engineered FokI cleavage half-domain, wherein the engineered cleavage half-domain comprises: a) substituting the wild-type Gln residue at position 486 with a Glu residue, the wild-type Ile residue at position 499 with a Leu residue and the wild-type Asn residue at position 496 with an Asp or a Glu residue; or b) substituting the wild-type Glu residue at position 490 with a Lys residue, the wild-type Ile residue at position 538 with a Lys residue, and the wild-type His residue at position 537 with a Lys residue or a Arg residue; or c) substituting the wild-type Glu residue at position 490 with a Lys residue and the wild-type His residue at position 537 with a Lys residue or an Arg residue; or d) substituting the wild-type Arg residue at position 487 with an Asp residue and the wild-type Asn residue at position 496 with an Asp residue; or e) substituting the wild-type Arg residue at position 487 with an Asp residue, the wild-type Asn residue at position 496 with an Asp residue and the wild-type Ile residue at position 499 with an Ala; or f) substituting the wild-type Asp residue at position 483 with an Arg residue and the wild-type His residue at position 537 with an Arg residue; or g) substituting the wild-type Arg residue at position 487 with an Asp residue, the wild-type Asn residue at position 496 with an Asp residue and the wild-type His residue at position 537 with an Arg residue; or h) substituting the wild-type Asp residue at position 483 with an Arg residue, the wild-type Ile residue at position 538 with a Val residue and the wild-type His residue at position 537 with an Arg residue, wherein the amino acid residues are numbered relative to a full length FokI wild-type cleavage domain as shown in SEQ ID NO:57. (i) a DNA-binding domain that binds to a target site in the genome of the cell; and (ii) a polypeptide comprising an engineered FokI cleavage half-domain, wherein the engineered cleavage half-domain comprises: a) substituting the wild-type Gln residue at position 486 with a Glu residue, the wild-type Ile residue at position 499 with a Leu residue and the wild-type Asn residue at position 496 with an Asp or a Glu residue; or b) substituting the wild-type Glu residue at position 490 with a Lys residue, the wild-type Ile residue at position 538 with a Lys residue, and the wild-type His residue at position 537 with a Lys residue or a Arg residue; or c) substituting the wild-type Glu residue at position 490 with a Lys residue and the wild-type His residue at position 537 with a Lys residue or an Arg residue; or d) substituting the wild-type Arg residue at position 487 with an Asp residue and the wild-type Asn residue at position 496 with an Asp residue; or e) substituting the wild-type Arg residue at position 487 with an Asp residue, the wild-type Asn residue at position 496 with an Asp residue and the wild-type Ile residue at position 499 with an Ala; or f) substituting the wild-type Asp residue at position 483 with an Arg residue and the wild-type His residue at position 537 with an Arg residue; or g) substituting the wild-type Arg residue at position 487 with an Asp residue, the wild-type Asn residue at position 496 with an Asp residue and the wild-type His residue at position 537 with an Arg residue; or h) substituting the wild-type Asp residue at position 483 with an Arg residue, the wild-type Ile residue at position 538 with a Val residue and the wild-type His residue at position 537 with an Arg residue, a) substituting the wild-type Gln residue at position 486 with a Glu residue, the wild-type Ile residue at position 499 with a Leu residue and the wild-type Asn residue at position 496 with an Asp or a Glu residue; or b) substituting the wild-type Glu residue at position 490 with a Lys residue, the wild-type Ile residue at position 538 with a Lys residue, and the wild-type His residue at position 537 with a Lys residue or a Arg residue; or c) substituting the wild-type Glu residue at position 490 with a Lys residue and the wild-type His residue at position 537 with a Lys residue or an Arg residue; or d) substituting the wild-type Arg residue at position 487 with an Asp residue and the wild-type Asn residue at position 496 with an Asp residue; or e) substituting the wild-type Arg residue at position 487 with an Asp residue, the wild-type Asn residue at position 496 with an Asp residue and the wild-type Ile residue at position 499 with an Ala; or f) substituting the wild-type Asp residue at position 483 with an Arg residue and the wild-type His residue at position 537 with an Arg residue; or g) substituting the wild-type Arg residue at position 487 with an Asp residue, the wild-type Asn residue at position 496 with an Asp residue and the wild-type His residue at position 537 with an Arg residue; or h) substituting the wild-type Asp residue at position 483 with an Arg residue, the wild-type Ile residue at position 538 with a Val residue and the wild-type His residue at position 537 with an Arg residue,