Most studies that have focused on female serial killers (FSKs), although informative, have examined limited sample sizes. We consulted mass media reports of demographics, motives, methods, mental health, and victim characteristics of 64 FSKs who committed their crimes in the US from 1821 to 2008. Consistent with other studies, our data showed that FSKs were typically White, educated, have been married, and held a caregiving role (e.g. mother, health care worker). Nearly 40% of FSKs in this sample experienced some form of mental illness. Their most common motive for murder was financial gain, and their most common method of killing was poisoning. FSKs knew all or most of their victims, and most were related to their victims. In all cases, FSKs targeted at least one victim who was a child, elderly, or infirm – those who had little chance of fighting back. We interpret these killers’ behaviors from clinical and evolutionary angles.