Skin is a complex tissue whose biomechanical properties are generally understood in terms of an incompressible material whose microstructure undergoes affine deformations. A growing number of experiments, however, have demonstrated that skin has a high Poisson's ratio, substantially decreases in volume during uniaxial tensile loading, and demonstrates collagen fiber kinematics that are not affine with local deformation. In order to better understand the mechanical basis for these properties, we constructed multiscale mechanical models (MSM) of mouse skin based on microstructural multiphoton microscopy imaging of the dermal microstructure acquired during mechanical testing. Three models that spanned the cases of highly aligned, moderately aligned, and nearly random fiber networks were examined and compared to the data acquired from uniaxially stretched skin. Our results demonstrate that MSMs consisting of networks of matched fiber organization can predict the biomechanical behavior of mouse skin, including the large decrease in tissue volume and nonaffine fiber kinematics observed under uniaxial tension.