ALK translocation amounts to around 3–7% of all NSCLCs. The clinical features of ALK+ NSCLC are an adenocarcinoma histology, younger age, limited smoking history, and brain metastases. The activity of chemotherapy and immunotherapy is modest in ALK+ disease. Several randomized trials have proven that ALK inhibitors (ALK-Is) have greater efficacy with respect to platinum-based chemotherapy and that second/third generation ALK-Is are better than crizotinib in terms of improvements in median progression-free survival and brain metastases management. Unfortunately, most patients develop acquired resistance to ALK-Is that is mediated by on- and off-target mechanisms. Translational and clinical research are continuing to develop new drugs and/or combinations in order to raise the bar and further improve the results attained up to now. This review summarizes first-line randomized clinical trials of several ALK-Is and the management of brain metastases with a focus on ALK-I resistance mechanisms. The last section addresses future developments and challenges.