Like other systemic chemotherapies, cancer cell develops PARPi resistance via several different mechanisms: (i) increased expression of multidrug resistance pumps (MDRs), enhancing the efflux of the PARPi out of the cell [263], (ii) reduced PARP1 binding affinity to DNA due to mutations and functional alterations of the PARP1 protein and/or disrupted PARylation [264,265], or (iii) restored HR and/or replication fork stabilization [266,267,268,269]. The gene discussed is PARP1; the disease is cancer.