<p>Bruton's tyrosine kinase (BTK) inhibitors are transforming chronic lymphocytic leukemia (CLL) treatment. Given the availability of both covalent and non-covalent BTK inhibitors (BTKis) CLL treatment has become more nuanced. Here the mechanisms of action, efficacy, and resistance patterns associated with both inhibitor classes are reviewed to help create a framework for integrating covalent and non-covalent BTKis into CLL treatment algorithms. Our treatment algorithm based on the available data is as follows, in the frontline setting when oral therapy is preferred/chosen and indefinite therapy is not a deterrent, irrespective of DNA and IGVH mutational status, a second-generation covalent BTK inhibitor (cBTKi) is recommended. In the relapsed/refractory setting when oral therapy is preferred a second-generation cBTKi is preferred. For those suffering disease progression during second generation cBTK, it is recommended to change to an alternative cBTKi and for those exposed to greater than two lines of therapy, challenging to a non-covalent BTKi (ncBTKi) in the form of pirtobrutinib. At the time of disease progression on a BTKi, we recommend testing for resistance mutations. Data on combination therapy's role and time-limited BTKi use remain under active investigation.</p>