Pluripotent stem cells (PSCs) have enormous potential in the biomedical sciences because they can grow continuously and differentiate into any kind of cell in the body. However, for future application in regenerative medicine, it is still a challenge to control the differentiation of PSCs without using genetic materials. To control the differentiation of PSCs, small molecules might be the best substitute for genetic materials considering the following advantages: small size, which enables penetration of plasma membrane; easy-to-modify structure; and low chance of genetic recombination in treated cells. Herein, we introduce small molecules that induce the neuroectodermal differentiation of mouse embryonic stem cells (ESCs). The small molecules were identified via ESC-based consecutive screenings of small-molecule libraries composed of 324 natural compounds or 93 selected drugs. The natural compounds discovered in the first screening were used to select 93 structurally similar drugs out of 1,200 approved drugs. In the second screening, among the 93 compounds, we found 4 drugs that induced the neuroectodermal differentiation of ESCs. These drugs were progesteroneor corticoid-derivatives. Our results suggest that small molecules targeting the progesterone receptor or glucocorticoid receptor could be used as chemical tools to induce the differentiation of PSCs into a specific germ lineage.