Olomoucine and Roscovitine are two ATP-competing compounds described as specific inhibitors of cyclin-dependent kinases (CDK). Both drugs showed to induce apoptosis in SH-SY5Y, a neuroblastoma-derived cell line. In these cells, neither Bcl-2 nor Bcl-XL overexpression conferred any resistance to both drugs. However, a partial protective effect was detected when cells were treated with a general inhibitor of caspases (zVADfmk), cycloheximide (CHX), or actinomycin D (DAct). Interestingly, a synergism in cell protection was observed between zVADfmk and macromolecular synthesis inhibitors, thus suggesting different apoptotic pathways in distinct subpopulations of the cell culture. On the other hand, no lethality was found when cells were treated with either PD98059 or UO126. This discarded Erk1/Erk2 inhibition as the cause of apoptosis. Furthermore, SH-SY5Y cells became resistant to either Olomoucine or Roscovitine upon the induction of differentiation. This resistance correlated with the extent of differentiation and, therefore, the number of cells entering a quiescent state. In conclusion, our results seem to support a role for CDK inhibition as the cause of the apoptotic process triggered by Olomoucine and Roscovitine. In addition, we contribute to define a promising profile as anticancer drugs for both compounds, at least in the treatment of neuroblastoma.