Abstract: The invention provides methods for designing polynucleotide primers and probes that are optimized for hybridizing to a plurality of target nucleic acid variants by employing scoring and/or ranking steps that provide a positive or negative preference or “weight” to certain nucleotides in a candidate nucleic acid sequence. The particular scoring or ranking steps performed depend upon the intended use for the primer and/or probe, the particular target sequence, and the number of variants of that target sequence. The methods of the invention provide optimal primer and probe sequences because they hybridize to more target nucleic acid variants than primers and probes in the prior art.