In chronic lymphocytic leukemia (CLL), a deeper understanding of the disease biology led over the last decade to the development and clinical use of different targeted drugs, including Bruton tyrosine kinase (BTK) inhibitors. The first BTK inhibitor approved for clinical use is ibrutinib, which showed excellent efficacy and good tolerability. More recently, the interest is growing for novel more selective BTK inhibitors that may reduce the off-target effects of the drug, thus minimizing side effects and subsequent treatment interruptions or discontinuations. Acalabrutinib is an orally administered irreversible BTK inhibitor, characterized by the lack of inhibition towards other kinases. In this review, we present the most recent data from clinical trials on the clinical efficacy of acalabrutinib and acalabrutinib-based combinations for the treatment of patients with relapsed/refractory and treatment-naïve CLL. We delineate the safety profile of the drug, describe side effects of interest and discuss the clinical management of patients receiving acalabrutinib. Due to its efficacy and the favorable safety profile, acalabrutinib has emerged as a viable therapy option in the current landscape of multiple approved treatments for CLL.