Detecting early signs of autism is essential for timely diagnosis and initiation of effective interventions. Several research groups have initiated prospective studies of high-risk populations including infant siblings, to systematically collect data on early signs within a longitudinal design. Despite the potential advantages of prospective studies of young children at high-risk for autism, there are also significant methodological, ethical and practical challenges. This paper outlines several of these challenges, including those related to sampling (e.g., defining appropriate comparison groups), measurement and clinical implications (e.g., addressing the needs of infants suspected of having early signs). We suggest possible design and implementation strategies to address these various challenges, based on current research efforts in the field and previous studies involving high-risk populations.