Long-acting drug nanosuspension formulations are coming to the fore as controlled release strategies for several medical conditions and as a preventative measure against HIV infection. However, such delivery systems must, by necessity, be given by hypodermic injection, typically into muscle. This poses problems for patients who are needle-phobic, given that injections have to be administered on a weekly or monthly basis. Needle-stick injuries, inappropriate reuse of needles, and poor disposal practices are major challenges in developing countries. Dissolving microneedles (MNs) are capable of delivering high drug doses, if suitably designed and formulated, and are also capable of delivering nanoparticles (NPs) into viable skin. Given that such microneedles are minimally invasive and self-disabling, the potential for major enhancement in patient care and compliance exists. In this review, we explore the key considerations in the development of these combination drug delivery systems.