If a person requires a tissue donation in order to survive, many philosophers argue that whatever moral responsibility a biological relative may have to donate to the person in need will be grounded at least partially, if not entirely, in the biological relations the potential donor bears to the recipient. Such views tend to ignore the role played by a potential donor’s unique ability to help the person in need and the perceived burden of the donation type in underwriting such judgments. If, for example, a sperm donor is judged to have a significant moral responsibility to donate tissue to a child conceived with his sperm, we argue that such judgments will largely be grounded in the presumed unique ability of the sperm donor to help the child due to the compatibility of his tissues with those of the recipient. In this paper, we report the results of two main studies and three supplementary studies designed to investigate the comparative roles that biological relatedness, unique ability to help, and donation burden play in generating judgments of moral responsibility in tissue donation cases. We found that the primary factor driving individuals’ judgments about the moral responsibility of a potential donor to donate tissue to someone in need was the degree to which a donor was in a unique ability to help. We observed no significant role for biological relatedness as such. Biologically related individuals were deemed to have a significant moral responsibility to donate tissue only when they are one of a small number of people who have a relatively unique capacity to help. We also found that people are less inclined to think individuals have a moral responsibility to donate tissue when the donation is more costly to make. We bring these results into dialogue with contemporary disputes concerning the ethics of tissue donation.