The adoption of large language models (LLMs) and autonomous agents in software engineering marks an enduring paradigm shift. These systems create new opportunities for tool design, workflow orchestration, and empirical observation, while fundamentally reshaping the roles of developers and the artifacts they produce. Although traditional empirical methods remain central to software engineering research, the rapid evolution of AI introduces new data modalities, alters causal assumptions, and challenges foundational constructs such as “developer”, “artifact”, and “interaction”. As humans and AI agents increasingly co-create, the boundaries between social and technical actors blur, and the reproducibility of findings becomes contingent on model updates and prompt contexts. This vision paper examines how the integration of LLMs into software engineering disrupts established research paradigms. We discuss how it transforms the phenomena we study, the methods and theories we rely on, the data we analyze, and the threats to validity that arise in dynamic AI-mediated environments. Our aim is to help the empirical software engineering community adapt its questions, instruments, and validation standards to a future in which AI systems are not merely tools, but active collaborators shaping software engineering and its study.