The licensing framework established by the U.S. Nuclear Regulatory Commission under Title 10 of the Code of Federal Regulations (10 CFR) Part 52, “Licenses, Certifications, and Approvals for Nuclear Power Plants,” provides requirements for standard design certifications (DCs) and combined license (COL) applications. The intent of this process is the early resolution of safety issues at the DC application stage. Subsequent COL applications may incorporate a DC by reference. Thus, the COL review will not reconsider safety issues resolved during the DC process. However, a COL application that incorporates a DC by reference must demonstrate that relevant site-specific design parameters are confined within the bounds postulated by the DC, and any departures from the DC need to be justified. This paper provides an overview of structural design challenges encountered in recent DC applications under the 10 CFR Part 52 process, in which the authors have participated as part of the safety review effort.