Research on palliative care presents some unique sampling challenges. The purpose of this paper is to articulate the sampling challenges that palliative care researchers face during phases of study design, conduct, and the reporting of results. Challenges include identifying a target population, avoiding selection bias in the face of clinician and patient denial of serious illness, developing eligibility criteria for a seriously ill population, minimizing high patient refusals due to illness, and accurate reporting of all screened and eligible participants. These challenges are explored within the context of a randomized clinical trial testing a palliative care intervention. Suggestions for improving scientific rigor in sampling design include 1) defining a target population that is consistent with research goals; 2) identifying eligibility criteria that are objective and understandable to clinicians to yield the desired sample; and 3) reporting results about the target population, sample eligibility/exclusions, and participation using standardized criteria.