In eukaryotic cells, each phase of the cell division cycle is controlled by the sequential activation of various cyclin-dependent kinases (Cdks). These kinases are known to phosphorylate various substrates whose activity is critical for cell cycle progression. As key regulators of the cell cycle, Cdks must be strictly controlled by both extracellular and intracellular signals for adequate responses to occur. There are several distinct molecular mechanisms for controlling the activity of the different Cdks: regulated synthesis and destruction of the activating subunit (cyclin), regulated synthesis and destruction of the inhibitory subunit (Cki), and posttranslational modification of the kinase subunit by highly specific kinases and phosphatases. During the G1 phase of the cell cycle, cells sense, integrate positive and negative signals, and transmit them to the cell cycle machinery. Because of this pivotal role, a vast majority of oncogenic events selectively target elements controlling the G1. In this review we discuss the elements controlling the G1 phase in relationship to the genesis of cancer.