The gastrointestinal ecosystem is formed from interactions between the host, indigenous gut microbiota, and external world. When colonizing the gut, bacteria must overcome barriers imposed by the intestinal environment, such as host immune responses and microbiota-mediated nutrient limitation. Thus, understanding bacterial colonization requires determining how the gut landscape interacts with microbes attempting to establish within the ecosystem. However, the complicated network of interactions between elements of the intestinal environment makes it challenging to uncover emergent properties of the system using only reductionist methods. A systems biology approach, which aims to investigate complex systems by examining the behavior and relationships of all elements of the system, may afford a more holistic perspective of the colonization process. Here, we examine the confluence between the gut landscape and bacterial colonization through the lens of systems biology. We offer an overview of the conceptual and methodological underpinnings of systems biology, followed by a discussion of key elements of the gut ecosystem as they pertain to bacterial establishment and growth. We conclude by reintegrating these elements to guide future comprehensive investigations of the ecosystem in the context of bacterial intestinal colonization.