Tissue engineering scaffolds must define shape for anatomic tissue regeneration, provide temporary mechanical support, and enhance tissue regeneration through delivery of biologics and a suitable mass transport environment. Scaffold material and 3D porous architecture design will determine how well the scaffold can fulfill these requirements. Optimizing scaffold design will require experiments that specifically test how variations in scaffold material and architecture affect mechanical properties, mass transport properties and tissue regeneration. These issues have been studied intensively for bone formation during the past decade (see for example, Karageorgiou et al., 2005; Otsuki et al., 2006; Li et al., 2007). These studies have concluded that well connected pore structures favor bone regeneration independent of pore size. However, this conclusion could only be confirmed with the capability to design and fabricate scaffolds with reproducible and rigorously controlled pore architectures. By comparison, there is much less research regarding how scaffold material and architecture design affect soft tissue regeneration. Soft tissue regeneration represents a much larger array of tissue engineering applications including cartilage, fibrocartilaginous tissues, cardiovascular tissues, neural tissues, ligaments, tendons, and skeletal muscle.Whereas for bone, one may define osteoconductive materials (LeGeros, 2002) that favor bone regeneration, it does not appear that comparable chondroconductive or neuroconductive definitions exist. Furthermore, while one could argue that the necessity for high pore connectivity for bone regeneration is intuitive based on bone being a highly metabolically active tissue, soft tissues have a wide array of metabolic activity ranging from cartilage (low) toCNS (medium) to skeletal muscle (high). (Table presented) This metabolic activity could be related to tissue permeability, which also ranges from cartilage having a low value at 2.5e -15 m4/Ns (Demarteau et al., 2006) to brain tissue at 7e-13 m4/Ns (Linninger et al., 2007) to bone having a high value at 1e-7 m4/Ns (Kohles et al., 2001). Additionally, soft tissue mechanical properties are extremely varied, with complex nonlinear elastic and viscoelastic behavior. A widely used 1D nonlinear elastic model for soft tissues is S = A(eBε?1), where A, B are fit coefficients, ε is the large strain tensor and S is the 1st Piola-Kirchoff stress. The tangent modulus for this model is E = ABeBε. Fitting soft tissue experimental data to this model shows the broad range of soft tissue mechanical properties (Table 5.1). Given the large tissue engineering literature in soft tissue regeneration, we will focus on cartilage and central nervous system (CNS) tissue applications in this chapter. Specifically, this chapter will present results on designed scaffolds with controlled mass transport and mechanical properties, and how these controlled scaffold architectures influence cartilage and CNS tissue regeneration.