Nature produces a multitude of composite materials with intricate architectures that in many instances far exceed the performance of their modern engineering analogs. Despite significant investigations into structure-function relationships of complex biological materials, there is typically a lack of critical information regarding the specific functional roles of many of their components. To help resolve this issue, the authors present here a framework for investigating biological design principles that combines parametric modeling, multi-material 3D printing, and direct mechanical testing to efficiently examine very large parameter spaces of biological design. Using the brick and mortar-like architecture of mollusk nacre as a model system, the authors show that this approach can be used to effectively examine the structural complexity of biological materials and harvest design principles not previously accessible.Biological systems continue to serve as sources of inspiration for innovative materials design as they often feature surprising combinations of properties owing to their hierarchical and multiphase architectures.[1] While many attempts have been made at adapting these biological design strategies to solving real world engineering problems, [1b,2] the fact that biology is characterized by multi-purpose systems that interact in complex ways, makes it challenging to tease apart specific cause and effect relationships in biological materials design. If we are to succeed in mimicking biology in order to achieve a specific performance metric, it is necessary to establish relationships that identify the design parameters that are essential to materials' mechanical performance and not simply artifacts of growth processes or evolutionary baggage (i.e., features maintained in current populations but no longer advantageous to species' fitness). Our limitations in translating biological designs are in very large part due to the lack of efficient and high resolution methods for querying the 3D "structural parameter space" of biological systems -the range of observed and/or possible biological morphologiesto allow distillation of the most decisive features.To this end, we have developed a new framework for the study of biological materials design, combining parametric modeling, multi-material 3D printing, and direct mechanical testing (Figure 1), thereby adding to previously developed methodologies.[3] Specifically, this modified framework allows for investigations of 3D biological structures in a systematic and parametric manner, whereas previous methods have focused on the correlation between 2D computational models and the mechanical behavior of their 3D-printed analogs (i.e. 2D models extruded into 3D).