The discovery of the EML4-ALK fusion gene in a limited subset of non-small-cell lung cancer (NSCLC) patients and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistance to crizotinib regularly develops ultimately leading to disease progression. Since then, several novel ALK targeting tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, lorlatinib and ensartinib have been developed. While initially showing their worth in the second line treatment of ALK-positive advanced NSCLC, more recent studies have also demonstrated superior efficacy of second-generation ALK inhibitors over crizotinib in the first-line treatment of these patients. As a result, second-generation ALK inhibitors have largely replaced crizotinib as the preferred first-line treatment for patients with advanced ALK-positive NSCLC. In this article we want to provide an overview of the current evidence on the best sequence in the treatment of ALK-positive NSCLC patients.