Clinical application of single-cell technologies for CLL. Single-cell approaches allow for deeper characterization of leukemic and immune cells to help aid prognostication, optimize and rationalize treatments, and modulate the immune system to enhance potential immunotherapeutic approaches at diagnosis and relapse. At diagnosis or during follow-up, monitoring can identify clones that represent higher risk, and appropriate treatment can be instituted or defects within immune cells can be characterized and then addressed. After treatment, single-cell approaches have the potential to detect relapse earlier, identify the underlying resistance-driving mutations, and select the optimum strategy for overcoming the problem. An ever-present clinical concern is Richter’s transformation, in which single-cell approaches may also be able to help with earlier diagnosis and treatment optimization. This approach is not limited to CLL but has applicability across the range of hematologic malignancies. PFS, progression-free survival; OS, overall survival; WBC, white blood cell.