: PI3K inhibition with idelalisib (at that time CAL-101) was at the forefront of the development of molecularly targeted therapies in Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) and follicular lymphoma. However, after initial approval, subsequent trials identified specific immune-mediated and infectious toxicity that led to a reduced use and stopped the further development of this agent. PI3K inhibition as a treatment paradigm fell out of favor compared to other developments such as BTK or BCL2 inhibitors.: This review provides an overview of the experience with approved PI3Ki, including long-term experience, and highlights the current PI3Ki developments in CLL, B-cell and T-Cell Non-Hodgkin’s Lymphoma.: With careful monitoring and prophylaxis usage of the first-generation PI3K inhibitor, idelalisib, in the approved indications, it is safe and remains an option in higher line therapy after the failure of other novel agents and/or chemoimmunotherapy. New developments with next-generation PI3K inhibitors of improved tolerability and sustained efficacy reignited the treatment principle and already led to newly approved therapeutic options for patients. Certainly, the authors here believe that PI3K inhibitors as a monotherapy and in combination with other agents is currently a rapidly evolving field in cancer treatment.