Twenty-one percent of transplants in the US come from live donors. Data show that live-donor transplantation is a safe practice, but is not completely risk free. Malignancy and infection transmission through live organ donation is extremely rare, but can be a devastating event for the recipient, donor and treatment team if it occurs. The donor evaluation is multifactorial, taking into the account the unique medical, social and family history of individual donors, needs of the recipient, and determination of the anatomic and functional suitability of the donor organ, and is further complicated by geographical and temporal components. While balancing all practical considerations can be complex, a thorough medical assessment for infection and malignancy of potential living donor is central in protecting the donor and the intended transplant recipient.