Low-penetrance genetic variations appear to form the most essential component of the heritability of cancer risk. Search for relevant polymorphic candidates faces significant obstacles, due to both the high number of potentially promising single nucleotide polymorphisms (SNPs) and the intrinsic difficulties in identification of weak gene-disease interactions. At present, extensive case-control studies can be applied only to a limited number of gene polymorphisms. Therefore, the choice of SNPs that deserve an exhaustive populational analysis is of primary importance. Preferences are usually given to those genetic pathways, whose variability and role in cancer causation have been already shown by prior studies. The available electronic databases and software tools may allow further SNP sorting, based on functional predictions. The design for the pilot study may need to be different from the one for large-scale case-control analysis. Some investigations justify non-random patient selection for preliminary assessment of low-penetrance effects, with the emphasis on particularly susceptible individuals (familial, early onset, multiple cancer cases). Other presumably accelerating approaches suggest a decisive exclusion of SNP candidates showing only marginal effects, relaxed formats for rapid dissemination of preliminary data, use of more demonstrative controls such as elderly tumor-free subjects, etc. These short-cuts cannot be properly validated for the time being, due to the paucity of identified low-penetrance risk modifiers. It is expected that the increasing capacities of available DNA collections, coupled with the rapid development of high-throughput genotyping technologies, will vastly accelerate the research on polygenic cancer susceptibility.