Cell cycle deregulation is one of the first steps that transform normal cells into tumor cells. CDKs are a family of proteins devoted to controlling cell cycle entry, progression and exit. Studies from animal models show a tissue-specific essentiality of the single CDKs. In cancer cells, mis-regulation of CDK function is a common event. For this reason the pioneer compound Flavopiridol was developed and many new drugs are currently under development. ATP and the last generation of non-ATP competitive inhibitors are now emerging as one of the most potentially powerful target therapies. Many clinical trials are ongoing, as either a single agent or in combination with the classical cytotoxic agents. In this review, we discuss new strategies and methods to design more potent, selective and specific CDK inhibitors, starting from evidence emerging from animal and cancer cell models.