ABL1 and FLT3 are two kinases that become overactive in leukaemias. Constitutively active ABL1 is the hallmark of chronic myeloid leukaemia (CML), whereas mutations in the gene encoding FLT3 are seen in 35% of the patients that suffer from acute myeloid leukaemia (AML). Inhibitors of these kinases are used to treat these leukaemias, but the development of resistance is common. The main cause of resistance in both cases are mutations in the gene encoding the target protein. While one would expect that resistance mutations interfere with protein-drug interactions directly, this is oftentimes not the case. The mutations can have different working mechanisms, such as making the enzyme adopt a conformation that does not bind the drug or which make it more efficient. We used a computational approach to study the effect of resistance mutations with computer simulations, ranging from classical molecular dynamics (MD) to more advanced methods that involve enhanced sampling. Our efforts led to a better understanding of these mutations and their effects on the molecular level. Some of these studies were followed up by enzymatic assays in the lab. In parallel to our studies of resistance mutations, we have also followed on the mechanism of enzyme activation. Using enhanced sampling methods we could decipher how these two enzymes become activated, something that could not be understood solely from experiments. Overall, our studies contributed to a better understanding of (pathological) enzyme activation and drug resistance from a molecular point of view, and provide useful set-up for the development of better drugs in CML and AML