Screening for genetic variants that predispose individuals or their offspring to disease may be performed at the general population level or may instead be targeted at the relatives of previously identified carriers. The latter strategy has come to be known as "cascade genetic screening." Since the carrier risk of close relatives of known carriers is generally higher than the population risk, cascade screening is more efficient than population screening, in the sense that fewer individuals have to be genotyped per detected carrier. The efficacy of cascade screening, as measured by the overall proportion of carriers detected in a given population, is, however, lower than that of population-wide screening, and the respective inclusion rates vary according to the population frequency and mode of inheritance of the predisposing variants. For dominant mutations, we have developed equations that allow the inclusion rates of cascade screening to be calculated in an iterative fashion, depending upon screening depth and penetrance. For recessive mutations, we derived only equations for the screening of siblings and the children of patients. Owing to their mathematical complexity, it was necessary to study more extended screening strategies by simulation. Cascade screening turned out to result in low inclusion rates (<1%) when aimed at the identification of heterozygous carriers of rare recessive variants. Considerably higher rates are achievable, however, when screening is performed to detect covert homozygotes for frequent recessive mutations with reduced penetrance. This situation is exemplified by hereditary hemochromatosis, for which up to 40% of at-risk individuals may be identifiable through screening of first- to third-degree relatives of overt carriers (i.e., patients); the efficiency of this screening strategy was found to be approximately 50 times higher than that of population-wide screening. For dominant mutations, inclusion rates of cascade screening were estimated to be higher than for recessive variants. Thus, some 80% of all carriers of the factor V Leiden mutation would be detected if screening were to be targeted specifically at first- to third-degree relatives of patients with venous thrombosis. The relative cost efficiency of cascade as compared with population-wide screening (i.e., the overall savings in the extra managerial cost of the condition) is also likely to be higher for dominant than for recessive mutations. This notwithstanding, once screening has become cost-effective at the population level, it can be expected that cascade screening would only transiently represent an economically viable option.