Aligning Clinical and Translational Research (CTR) methods and the CTSA consortium within a larger Learning Health System can drive research and improve use of health care information to advance knowledge and improve practice. To do this, CTR must rely on a complex array of methods, ranging from new study designs to high-dimensional data analysis, causal inference, mediation analysis, and Bayesian inference methods. Because methodologic research is a key aspect of CTR, it is important to attract the best statisticians and epidemiologists to CTR, and to nurture their professional development. Knowledge of the regulations and the ability to navigate the ethical and compliance landscapes are also essential to CTR. The past few years have seen significant changes in the regulatory framework, from NIH data sharing mandates, to the 21st Century Cures Act, to patient “right to try” legislation and the 2018 revisions to the Common Rule regulations. Our proposed Research Methods encompass the aims and approaches of the Biostatistics, Epidemiology and Research Design (BERD) and Ethics, Regulatory Knowledge, and Support (ERKS) Cores. These essential cores lead critically important activities in support of the aims of the Center for Clinical and Translational Science and Training (CCTST). BERD and ERKS are highly integrated across the CCTST, and their goals align with those of the overall CCTST. To engage stakeholders, the BERD Core will provide expert consultation and focused collaboration with meritorious projects, and actively contribute to, and lead, the BERD community in the CTSA Consortium. The ERKS Core will build an Ethics Center that encompasses all stakeholders and enhances the informed consent process. To promote workforce development and diversity, the BERD Core will cultivate the community of CTR methodologists, fostering BERD faculty and staff development, and educate and train clinical and translational researchers in study design, data management, and data analysis. The ERKS Core will provide training and education and promote ethics and regulatory knowledge in professional development. To organize, integrate, and optimize data use, the BERD Core will provide expertise that supports research design, data management, and data analysis and promote the development and dissemination of new methods and processes. The ERKS Core will design and implement study startup procedures that facilitate single Institutional Review Board (IRB) review and accommodate other changes in the revised Common Rule.