Lung cancer is the most lethal common cancer worldwide. Lung adenocarcinoma is the most common lung cancer subtype and tends to be aggressive and resistant to chemotherapy. With few targeted treatment options available to patients, there is a need to develop new therapeutics that can stop its spread in the body. Identifying the invasion and migration mechanisms used by lung adenocarcinoma will help us understand it’s spread. Cellular and matrix elements of the tumor microenvironment directly impact tumor migration, but the field lacks information on how lung adenocarcinoma responds to microenvironmental stimuli. Furthermore, these stimuli – including cellular components and matrix characteristics – can have compounding effects that can change tumor migration and invasion behaviors. This dissertation describes the development of two 3D in vitro models for studying lung adenocarcinoma migration behaviors in response to matrix architecture, cancer associated fibroblasts, and macrophages. These models investigate how lung adenocarcinoma tumor cells interact with surrounding stromal cells in confined and unconfined 3D spaces and in collagen matrices of varying densities. Our findings suggest that matrix architecture can influence the migration behaviors of CAFs which, in turn, alter lung adenocarcinoma movement and invasion. Macrophages are also investigated as potential influencers in lung adenocarcinoma metastasis. A better understanding of lung adenocarcinoma’s migration and invasion mechanisms in response to its microenvironment could lead to new strategies for targeted lung adenocarcinoma therapies.