Evidence-centered design (ECD) is an orientation towards assessment development. It differs from conventional practice in several ways and consists of multiple activities. Each of these activities results in a set of useful documentation: domain analysis, domain modeling, construction of the assessment framework, and assessment implementation/delivery (Mislevy & Haertel, 2006). In this article we focus on the four primary challenges we have encountered in our work with ECD in the context of large-scale educational assessment. For each challenge, we identify potential mitigation strategies as well as research studies or other endeavors that we think are helpful in advancing the science of ECD. The challenges discussed are: integrating learning theory into assessment design; identifying the appropriate levels of specificity with which to document the claims and evidence; developing and evaluating task models; and strategically incorporating iteration into the design process. (Contains 2 tables, 3 figures, and 2 footnotes.)