The advent of targeted therapies has led to tremendous improvements in treatment options and their outcomes in the field of oncology. Yet, many cancers outsmart precision drugs by developing on-target or off-target resistance mechanisms. Gaining the ability to resist treatment is the rule rather than the exception in tumors, and it remains a major healthcare challenge to achieve long-lasting remission in most cancer patients. Here, we discuss emerging strategies that take advantage of innovative high-throughput screening technologies to anticipate on- and off-target resistance mechanisms before they occur in treated cancer patients. We divide the methods into non-systematic approaches, such as random mutagenesis or long-term drug treatment, and systematic approaches, relying on the clustered regularly interspaced short palindromic repeats (CRISPR) system, saturated mutagenesis, or computational methods. All these new developments, especially genome-wide CRISPR-based screening platforms, have significantly accelerated the processes for identification of the mechanisms responsible for cancer drug resistance and opened up new avenues for future treatments.