Due to the low incidence of anal cancer and generally high cure rates, few second-line treatment options have been evaluated in the setting of formal clinical trials. We briefly report two cases that were both found to have wild-type K-RAS, with no epidermal growth factor receptor amplification or evidence of prior persistent human papilloma virus infection. Both cases were treated with irinotecan and cetuximab with evidence of clinical benefit in the setting of a third recurrence, as well as evidence of response to other strategies employed in their management. These cases provide support for the suggestion that treatment planning in conjunction with molecular profiling may be beneficial in such uncommon clinical settings.