The National Assessment of Educational Progress Science Assessment has consistently revealed small gender differences on science content items but not on science inquiry items. This assessment differs from others in that respondents can choose “I don't know” rather than guessing. This paper examines explanations for the gender differences including (a) differential prior instruction, (b) differential response to uncertainty and use of the “I don't know” response, (c) differential response to figurally presented items, and (d) different attitudes towards science. Of these possible explanations, the first two received support. Females are more likely to use the “I don't know” response, especially for items with physical science content or masculine themes such as football. To ameliorate this situation we need more effective science instruction and more gender-neutral assessment items.