Most previous sample size calculations for case-control studies to detect genetic associations with disease assumed that the disease gene locus is known, whereas, in fact, markers are used. We calculated sample sizes for unmatched case-control and sibling case-control studies to detect an association between a biallelic marker and a disease governed by a putative biallelic disease locus. Required sample sizes increase with increasing discrepancy between the marker and disease allele frequencies, and with less-than-maximal linkage disequilibrium between the marker and disease alleles. Qualitatively similar results were found for studies of parent offspring triads based on the transmission disequilibrium test (Abel and Müller-Myhsok, 1998, Am. J. Hum. Genet. 63: 664–667; Tu and Whittemore, 1999, Am. J. Hum. Genet. 64: 641–649). We also studied other factors affecting required sample size, including attributable risk for the disease allele, inheritance mechanism, disease prevalence, and for sibling case-control designs, extragenetic familial aggregation of disease and recombination. The large sample-size requirements represent a formidable challenge to studies of this type. Genet Epidemiol 25: 136–148, 2003. Published 2003 Wiley-Liss, Inc.