For the Treatment for Adolescents With Depression Study (TADS), a cognitive-behavioral therapy (CBT) manual was developed with the aim of balancing standardization and flexibility. In this article, we describe the manual's case formulation procedures, which served as one major mechanism of flexibility in TADS CBT. We first describe the essential components of a cognitive-behavioral case formulation. We then present a rationale for including individualized case formulation in manual-based treatments and clinical effectiveness studies, and discuss the specific case of TADS. We illustrate case formulation in an effectiveness study with a composite “case” of a 15-year-old male treated with TADS CBT. Clinical implications and future directions are discussed.