Fundamental to the recently–proposed hypothesis that females mate with more than one male as a hedge against genetic incompatibility is the premise that mechanisms are available to polyandrous females which enable them to safeguard their reproductive investment against the threat of incompatibility between maternal and paternal genomes. Accumulation of sperm from several males shifts the arena for sexual selection from the external environment to the female reproductive tract where, we suggest, interactions at the molecular and cellular levels provide females with direct mechanisms for assessing genetic compatibility. We present examples from the literature to illustrate how sperm competition and female choice of sperm can enable polyandrous females to minimize the risk of fertilization by genetically–incompatible sperm. Polyandry and multiple paternity also create the opportunity to reduce the cost of genetic incompatibility by reallocation of maternal resources from defective to viable offspring. This is likely to be a critically important post–copulatory mechanism for viviparous females whose intimate immunological relationship with developing embryos makes them particularly vulnerable to genetic incompatibility arising from intragenomic conflict and other processes acting at the suborganismal level.