The medical and personal circumstances of older persons present challenges for designing and analyzing clinical research studies in which they participate. These challenges that elderly study samples present are not unique, but they are sufficiently distinctive to warrant deliberate and systematic attention. Their distinctiveness originates in the multifactorial etiologies of geriatric health syndromes and the multiple morbidities accruing with aging at the end of life. The objective of this article is to identify a set of statistical challenges arising in research with older persons that should be considered conjointly in the practice of clinical research and addressed systematically in the training of biostatisticians intending to work with gerontologists, geriatricians, and older study participants. The statistical challenges include design and analytical strategies for multicomponent interventions, multiple outcomes, state transition models, floor and ceiling effects, missing data, and mixed methods. The methodological and pedagogical themes of this article will be integrated by a description of a proposed subdiscipline of “gerontologic biostatistics” and supported by the introduction of new set of statistical resources for researchers working in this area. These conceptual and methodological resources have been developed in the context of several collaborating Claude D. Pepper Older Americans Independence Centers.