Candida auris is an emergent human fungal pathogen of growing concern due to common drug resistance to all major antifungal drug classes. Although resistance to amphotericin B (AMB) has been detected in 30 to 60% of clinical isolates of C. auris, mechanisms of AMB resistance remain poorly characterized. Here we present a large-scale investigation of how AMB resistance can be acquired through genetic adaptation. We typed 441 in vitro and in vivo evolved C. auris lineages from four AMB-susceptible clinical strains of different clades. We show a great diversity of acquired resistance responses with resistance magnitude- and strain-dependent fitness trade-offs. Genotyping and membrane sterol analyses of selected lineages show four major types of membrane sterol alterations. Using a novel, plasmid-based CRISPR-Cas9 allele editing method and Cas9-RNP meditated gene deletions, we show that AMB resistance can be acquired through variation in several sterol biosynthesis regulators including ERG6, NCP1, ERG11, ERG3, HMG1, ERG10 and ERG12. Additionally, we show how aneuploidies in chromosomes 4 and 6 emerge during AMB resistance evolution. By leveraging fitness trade-off phenotyping and mathematical modelling of the in vivo environment during treatment, we evaluated the potential of different mechanisms to establish resistant infections and discover a mechanism of fitness trade-off compensation. Variation in CDC25 substantially enhanced the capacity to establish a resistant infection and may have played a role in facilitating the sole documented clinical case of acquired AMB resistance during treatment in C. auris. In summary, our findings show that fitness trade-off compensation along with several sterol modulating mechanisms of acquired AMB resistance represent a potential risk for AMB treatment failure in the clinic.