Acalabrutinib was approved by the U.S. Food and Drug Administration (FDA) for treatment-naive (TN) and relapsed/refractory (R/R) use for patients with chronic lymphocytic leukemia (CLL) in November 2019 following the phase III ASCEND and ELEVATE-TN registration trials. Acalabrutinib is a second-generation Bruton tyrosine kinase inhibitor (BTKi) that was developed after ibrutinib, the first-in-class BTKi. Ibrutinib is usually well tolerated and provides durable remissions; however, some patients experience toxicities from the off-target effects that lead to treatment discontinuation. A recent press release of the phase III ELEVATE-RR trial comparing acalabrutinib to ibrutinib in relapsed high-risk CLL reported noninferior progression-free survival and statistically significantly lower rates of atrial fibrillation; however, publication of this data is pending. There is currently 53 months of follow-up for patients receiving acalabrutinib compared with 8 years for those on ibrutinib. Acalabrutinib is approved as monotherapy in the R/R or TN setting, and in the TN setting can be combined with the anti-CD20 monoclonal antibody obinutuzumab. The data for acalabrutinib development and clinical use are discussed in this review.