A method of selecting a modified membrane-spanning protein with one or more modulated functional properties, said method comprising: generating a polynucleotide library wherein a sufficient number of bases of a polynucleotide encoding said membrane-spanning protein and/or a sufficient number of amino acid residues of said membrane-spanning protein are randomly modified so as to modulate the functional properties thereof, inserting the modified polynucleotides of said polynucleotide library into a construct comprising: a signal sequence, a first marker sequence, wherein said first marker sequence is in-frame with said modified polynucleotide, is downstream of said modified polynucleotide, and encodes one or more genes that overcome the sensitivity of a host cell to the presence of selective pressure agent(s)/conditions, and optionally a second marker sequence, wherein said second marker sequence, when present, is in-frame with the polynucleotide, is downstream of said signal sequence, but upstream of said modified polynucleotide, thereby producing modified polynucleotide-containing constructs, transforming suitable host cells with the modified polynucleotide-containing constructs, and selecting those cells which survive exposure to said selective pressure agent(s)/conditions and identifying the modified polynucleotide-containing construct(s) contained therein; wherein the surviving cells contain a modified membrane-spanning protein having one or more improved functional properties relative to wild type. generating a polynucleotide library wherein a sufficient number of bases of a polynucleotide encoding said membrane-spanning protein and/or a sufficient number of amino acid residues of said membrane-spanning protein are randomly modified so as to modulate the functional properties thereof, inserting the modified polynucleotides of said polynucleotide library into a construct comprising: a signal sequence, a first marker sequence, wherein said first marker sequence is in-frame with said modified polynucleotide, is downstream of said modified polynucleotide, and encodes one or more genes that overcome the sensitivity of a host cell to the presence of selective pressure agent(s)/conditions, and optionally a second marker sequence, wherein said second marker sequence, when present, is in-frame with the polynucleotide, is downstream of said signal sequence, but upstream of said modified polynucleotide, thereby producing modified polynucleotide-containing constructs, a signal sequence, a first marker sequence, wherein said first marker sequence is in-frame with said modified polynucleotide, is downstream of said modified polynucleotide, and encodes one or more genes that overcome the sensitivity of a host cell to the presence of selective pressure agent(s)/conditions, and optionally a second marker sequence, wherein said second marker sequence, when present, is in-frame with the polynucleotide, is downstream of said signal sequence, but upstream of said modified polynucleotide, thereby producing modified polynucleotide-containing constructs, transforming suitable host cells with the modified polynucleotide-containing constructs, and selecting those cells which survive exposure to said selective pressure agent(s)/conditions and identifying the modified polynucleotide-containing construct(s) contained therein; wherein the surviving cells contain a modified membrane-spanning protein having one or more improved functional properties relative to wild type.