Recent follow-up analyses of the previous findings from the Women's Health Initiative and the Women's Health Initiative Memory Study confirmed some health benefits of estrogen-containing hormone therapy (HT) in women within 10 years from the onset of menopause. However, the potential risks associated with long-term administration of HT, such as breast cancer and stroke, remain a concern for therapy recipients, underlying the need for an alternative treatment that is functionally equivalent but with a greater safety profile. Owing to their structural and functional resemblance to mammalian estrogens and lack of evident adverse effects, research interest in plant-derived phytoestrogens has increased in the past decade. While multiple health-promoting benefits of phytoestrogens have been proposed from basic science, the clinical data remain inconclusive. This review provides a comparative analysis of human studies on the effects of soy-based isoflavones on cognition. Of the eight studies published in 2000-2007, seven were conducted in postmenopausal women, four of which revealed a positive impact of isoflavones on cognitive function. Multiple factors could have contributed to the discrepant outcomes across studies, such as variation in the composition of phytoestrogen interventions and the heterogeneous characteristics of the study population. Thus, a well-designed clinical study based on a standardized stable formulation in a well-characterized study population is required in order to reach a clinical consensus. A formulation composed of select estrogen receptor beta-selective phytoestrogens with a rationally designed composition would avoid the potential antagonism present in a mixture and thus enhance therapeutic efficacy. In addition, inclusion of equol in a study formulation offers a potential synergistic effect from equol in both equol-producing and nonproducing individuals, as well as added benefits for men. With respect to the design of study population, a clinically consistent effect could potentially be achieved by stratifying populations based on genotype, age, hormonal history and even diets. Development of an effective phytoestrogen formulation would benefit both women and men to prevent or treat hormone-dependent conditions and, most of all, to improve neurological health and reduce the risk of Alzheimer's disease.