Drug resistance is one of the primary obstacles in cancer chemotherapy. The causes of drug resistances are varied. The primary resistance attributed to genomic instability while alteration in membrane permeability of drug and inability to reach the target sites, drug inactivation by enzymes, mutation and altered expression of target proteins there by affecting drug target interactions are some of the mechanism of acquired drug resistance. In addition to genetic changes there are epigenetic changes or non mutational mechanisms which occur quickly in response to environmental changes. Normal tissues never develop resistance to chemotherapy, because they possess intact genetic machinery. Drug resistance in addition to reducing clinical effectiveness, result in early termination of treatment, reduced relapse free interval and survival. There are various methods for overcoming these major disadvantages of cancer chemotherapy. Combination chemotherapy with clear understanding of the biochemical, molecular and pharmacokinetic mechanisms of interaction between the individual drugs in a given combination is one method.Optimal cancer drug scheduling is also a strategy for controlling resistance to therapy. Control avenues of drug administration and dose intensification provide better outcome. Despite various measures to overcome drug resistance, the problem especially multidrug resistance is still casting its shadow in successful chemotherapy. A better understanding of mechanism of drug resistance, its genetic and epigenetic links will open up new avenues in circumventing this fundamental problem and prolong the life expectancy of the patient. This article gives an overview of drug resistance encountered in cancer chemotherapy.