Folate receptor-targeted (FRT) liposomes for carboplatin were developed and evaluated in FR-positive and FR-negative cell lines, KB and A549, respectively, for their cytotoxic effects. Significant enhancement in carboplatin potency and intracellular drug accumulation was observed in KB cells when treated with FRT liposomes, compared to free drug and non-targeted liposomes. No enhancement was observed in the FR-negative A549 cells. The increase in carboplatin potency was hypothesized to be associated with an increase in the formation of DNA-platinum adducts resulted from an increase in cellular accumulation of the drug. Surprisingly, FRT carboplatin liposomes showed significantly lower levels of DNA-platinum adducts in comparison to free drug. To elucidate this discrepancy, activation of extracellular signal-regulated protein kinase (ERK) was probed, which has been suggested as an alternative mechanism of carboplatin action. FRT liposomes loaded with carboplatin exhibited the highest level of ERK phosphorylation, and the cytotoxic effect of FRT carboplatin liposomes could be reversed by the MEK/ERK inhibitors, U0126 and PD98059. Importantly, empty FRT liposomes could significantly increase ERK phosphorylation in a concentration-dependent manner without causing toxicity to cells. For the first time, increased potency of carboplatin delivered by FRT liposomes was found to be associated with other molecular targets in addition to DNA-platinum adduct formation. Collectively, the current study suggests a novel mechanism by which FRT liposomes could sensitize cancer cells to drug treatment via modulation of ERK-related cell survival signals.