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Simple Summary: The phosphoinositide 3-kinase (PI3K) is a family of kinases that play a key role in the biology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3K demonstrated efficacy in the treatment of CLL, associated with significant adverse events that limited the clinical use of this drugs. In this review, we underlined the relevance of PI3K inhibitors in CLL, we collected recent data about the use of these molecules in clinical practice and in clinical trial discussing strategies for the management of adverse events, which could help to improve the use of these therapies in the treatment of CLL. Chronic lymphocytic leukemia (CLL) shows constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of the B-cell receptor (BCR) signaling. PI3K inhibitors have been evaluated in CLL therapy, bringing a new treatment opportunity for patients with this disease. Despite the proven therapeutic efficacy, the use of approved PI3K inhibitors is limited by severe immune-mediated toxicities and given the availability of other more tolerable agents. This article reviews the relevance of PI3K signaling and pharmacologic inhibition in CLL. Data on efficacy and toxicity of PI3K inhibitors are also presented, as well as strategies for overcoming barriers for their clinical use in CLL treatment. [ABSTRACT FROM AUTHOR]