Cryptococcus neoformans and Cryptococcus gatti are invasive fungi and the major species responsible for cryptococcosis. Lungs and brain are the main organs of infection, and cryptococcal meningoencephalitis develops as a result of hematogenous dissemination of inhaled Cryptococcus spp. from the lung to the central nervous system. They are rare in healthy individuals, while being commonly associated with HIV-infected patients and immunosuppressive individuals. These fungi are prevalent in certain regions of the world, and the most common modes of exposure are through contact with soil and bird droppings. These fungi also are found in decaying wood and in tree hollows. It is estimated that 245,000 cases of cryptococcosis occur worldwide every year causing 181,000 deaths. The majority of deaths occur in resource-limited countries where access to drugs is limited, and cost of effective treatments is high. Cryptococcosis has been creating a high impact on human health for decades, but the antifungals currently used in infected patients, such as amphotericin B, flucytosine and fluconazole, were launched only after the 1990s. Unfortunately, these drugs are toxic, not fully efficient, unavailable worldwide, or even worse; and can lead to resistance. This scenario encourages the urgency in developing new, more efficient and affordable drugs for treatment against cryptococcosis. These molecules may be used directly or in combination with traditional antifungals or considered as a precursor for developing more efficient molecules. This review attempts to summarize the main virulence factors present in Cryptococcus spp. and report the challenges concerning the search for new drugs aimed at improvement in therapy: shorter treatment time, lower risk of toxicity and minimizing the development of resistance.