High-entropy alloys represent a new paradigm for structural materials in extreme environments; however, these alloys are like their traditional dilute counterparts subject to strength-toughness trade-offs. Whereas alloys with the face-centered cubic (fcc) crystal structure have exceptional fracture resistance but low strength, those with the body-centered cubic (bcc) structure have exceptional strength but low toughness. To overcome these limitations, a mechanistic understanding of the origin of these properties is required. In fcc alloys, high toughness is achieved through a sequence of deformation mechanisms (dislocation glide followed by twinning and a phase transformation) that with increasing strain generate three-dimensional (3D) defect networks that simultaneously arrest and transmit dislocations. This sequence can be repurposed by additive manufacturing, a processing technique that allows carefully tailored microstructures to be inserted into the material that also act to impede and subsequently channel dislocations. This process allows for elevated initial strength, without inhibiting plastic deformation. In bcc alloys, on the other hand, toughness can be attained through compositional tuning which enables plastic deformation. In contrast to the fcc systems, a softening mechanism—kink band formation—distributes damage from a crack tip despite promoting necking in tension. These alloys can even suppress their ductile-to-brittle transition, inherent to bcc systems, by activating an inverted sequence of deformation mechanisms that begins with twinning and a transformation and ends with dislocation glide. This sequence effectively allows the material to rely on temperature-insensitive defects to dissipate damage.