Research conducted after the 1994 Northridge earthquake in the U.S. and the 1995 Kobe earthquake in Japan led to the development of today's pre-qualified beam-to-column connections for capacity-designed steel moment resisting frames (MRFs). Welded moment connections feature weld backing bars that should be removed after the execution of complete joint penetration groove welds at the bottom beam flange-to-column flange joint. On the other hand, advancements in steel and weld materials, as well as fabrication techniques, allow for the exploitation of simplified weld details at this location. In welded moment connections for seismic applications, the participation of the beam-to-column web panel zones in the energy dissipation is generally limited during an earthquake event. In such a design context, beam local buckling is likely even at modest lateral drift demands, thereby engendering structural repair costs in the aftermath of earthquakes. The primary reasons for such a seismic design practice are twofold. The first one relates to known limitations of panel zone design models that compromise our ability to effectively balance the seismic design of fully restrained beam-to-column connections. The second one relates to the panel zone kinking that could increase the fracture potential of beam-to-column connections. However, recent experiments in the literature provide controversial results regarding the same matter. This doctoral thesis aims at advancing the state-of-knowledge regarding the seismic design and behavior of steel MRFs with highly dissipative panel zones. A new panel zone design model was first developed. This model addresses the limitations of all available panel zone models in the literature. The model was validated thoroughly with about 100 available experiments that encompass a broad range of geometric parameters. The panel zone model can effectively enable a balanced seismic design of welded moment connections with inelastic panel zones. One step further, this thesis revisited the current detailing of welded connections. Simplifications in their fabrication process were proposed by intentionally keeping a customized beveled backing bar in place, without impairing the connection's ductility under cyclic loading. The proposed connection weld detail is substantiated by continuum finite element analyses and full-scale experiments on welded moment connections with highly dissipative panel zones. It is demonstrated that, contrary to the current design paradigm, a stable hysteretic response is achieved up until lateral drift demands of at least 7% rad, thereby diminishing the cyclic deterioration in story shear resistance. As such, the seismic stability of steel MRFs is only governed by global P-Delta effects. Quantitative seismic response characteristics of steel MRFs with highly dissipative panel zones through large-scale systel-level parametric studies were also provided. It is shown that steel MRFs with highly inelastic panel zones, have up to two times lower mean annual frequency of collapse than corresponding results with steel MRFs designed with the current status quo. It is also demonstrated that steel MRFs with inelastic panel zones, enjoy up to 50% reduction in residual story drift ratios at a design-basis earthquake; their beam-to-column connections do not experience fractures due to panel zone kinking; and local buckling in steel beams is very limited even at low probability of occurrence seismic events.