The treatment landscape of advanced non-small cell lung cancer (NSCLC) patients has dramatically changed over the past 10 years, particularly thanks to the advent and development of several tyrosine kinase inhibitors (TKI) targeting oncogenic drivers. Among them, patients bearing anaplastic lymphoma kinase (ALK) translocations, which are causative of 3-5% of all advanced NSCLC, have seen dramatically improved their clinical outcomes moving life expectancy at 5 years from less than 5% to 50%. In fact, multiple ALK inhibitors (ALKi) entered in the therapeutic algorithm of ALK+ patients, multiplying their treatment opportunities. Remarkably, in the near future we could take advantage of up to different 6 molecules for the first-line approach (crizotinib, ceritinib, alectinib, brigatinib, plus ensartinib and lorlatinib). Among available ALKi, brigatinib, a second-generation (2G) inhibitor, showed notable activity in this setting, also against central nervous system (CNS) disease, and a good safety profile, supporting its approval as upfront treatment based on the ALTA-1L trial results. With a peculiar profile of enzymatic targets, brigatinib represents a valuable opportunity in the ALK targeting journey, albeit having to balance its safety profile. The abundance of therapeutic options for these patients poses nontrivial questions; in absence of direct comparisons of efficacy is not easy to define the best approach and, more compelling, the correct administration sequence in order to give the best therapeutic chances to ALK+ lung cancer patients. In such wide variety of options, we reviewed the preclinical and clinical efficacy data of brigatinib, its pharmacological and safety profile, like also actual and potential future applications in the ALK+ NSCLC scenario. Through a spurious exercise of an indirect comparison with other available 2G ALKi, we tent to summarize the required knowledge to properly choose the best drug at the right time. Furthermore, we reviewed available data on molecular resistance mechanisms and putative therapeutic applications in other contexts, such as ROS1+ NSCLC patients or EGFR+ ones progressing to osimertinib.