The Hospital for Special Surgery (HSS) new River Building consists of eleven stories plus a mechanical penthouse covering a footprint area of approximately 8650 ft2 which will be connected to the existing HSS buildings. The River Building will span over the FDR Drive, one of the busiest roadways in Manhattan. The building frame consists of entirely structural steel with a total weight of approximately 2500 tons. This paper discusses the major challenges faced in designing and planning the construction of the new HSS building. Not only must the building span 100 ft across the FDR, but it is also required to maintain 20 ft clear height for underneath vehicles. This results in using a mix of transfer girders and multi-story high trusses along the north-south faces of the building in addition to moment frames to enable the structure to span over the FDR. Due to the sloping rock profile underneath the building and the limited footprint available for the foundations, a combination of reinforced concrete caissons with rock anchors are used on the east side. On the west side, spread footings bearing on shallow bedrock are used. Computation Fluid Dynamics (CFD) analysis is performed to demonstrate that the building is capable of withstanding an extreme event such as car fire right adjacent to the building. The CFD analysis results provided transient temperature variations for the exposed steel members. These data were then used to calculate the reduction in steel strength and stiffness. The reduction in steel material properties due to fire was considered in the analysis and design of the building for both strength and serviceability. The structural framing system is designed for off-site modular construction due to the limited work area available, crane pick limitations and to minimize disruption to the FDR. The modular construction plan involves utilizing the east river to transport pre-fabricated modules via a barge then lifting them into place above the FDR.