This report presents the evaluation approach developed for the DARPA Big Mechanism program, which aimed at developing computer systems that will read research papers, integrate the information into a computer model of cancer mechanisms, and frame new hypotheses. We employed an iterative, incremental approach to the evaluation of the three phases of the program. In Phase I, we evaluated the ability of system and human teams ability to read-with-a-model to capture mechanistic information from the biomedical literature, integrated with information from expert curated biological databases. In Phase II we evaluated the ability of systems to assemble fragments of information into a mechanistic model. The Phase III evaluation focused on the ability of systems to provide explanations of experimental observations based on models assembled (largely automatically) by the Big Mechanism process. The evaluation for each phase built on earlier evaluations and guided developers towards creating capabilities for the new phase. The report describes our approach, including innovations such as a reference set (a curated data set limited to major findings of each paper) to assess the accuracy of systems in extracting mechanistic findings in the absence of a gold standard, and a method to evaluate model-based explanations of experimental data. Results of the evaluation and supporting materials are included in the appendices.