Over the last decade, melanoma treatment has taken rapid strides with the advent of immunotherapies and targeted agents. With these new agents, there has been a significant improvement in patient survival. However, these new treatment options may sometimes lead to unanticipated side effects that make these treatments challenging to administer and monitor. In preclinical studies, BRAF and MEK inhibitors have shown to modulate tumor microenvironment and potentiate immunotherapies. Therefore, some patients who had prior treatment with immunotherapies can develop immune toxicities even with these targeted agents due to the long half-life of these monoclonal antibodies. Herein, we present our institutional experience with regard to these unexpected toxicities with targeted agents in patients who had previous treatment with immunotherapies. This case series lays out the various side effects along with details of their management, outcomes, and patient response.